View source for Gene therapy

{{Short description|Medical field}}
{{Use dmy dates|date=December 2022}}

[[File:Gene therapy.jpg|thumb|Gene therapy using an [[adenovirus]] vector. In some cases, the adenovirus will insert the new gene into a cell. If the treatment is successful, the new gene will make a functional [[protein]] to treat a disease.]]

{{Genetic engineering sidebar}}

'''Gene therapy''' is a [[Medicine|medical]] field which focuses on the genetic modification of cells to produce a therapeutic effect<ref>{{cite journal|last=Kaji|first=Eugene H.|date=7 February 2001|title=Gene and Stem Cell Therapies|journal=JAMA|volume=285|issue=5|pages=545–550|doi=10.1001/jama.285.5.545|pmid=11176856|issn=0098-7484|doi-access=free}}</ref> or the treatment of disease by repairing or reconstructing defective genetic material.<ref>{{cite book|title=Emerging Medical Technologies|last=Ermak|first=Gennady| name-list-style = vanc |publisher=World Scientific|year=2015|isbn=978-981-4675-81-9}}</ref> The first attempt at modifying human [[DNA]] was performed in 1980, by [[Martin Cline]], but the first successful nuclear gene transfer in humans, approved by the [[National Institutes of Health]], was performed in May 1989.<ref>{{cite journal | vauthors = Rosenberg SA, Aebersold P, Cornetta K, Kasid A, Morgan RA, Moen R, Karson EM, Lotze MT, Yang JC, Topalian SL | display-authors = 6 | title = Gene transfer into humans – immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction | journal = The New England Journal of Medicine | volume = 323 | issue = 9 | pages = 570–578 | date = August 1990 | pmid = 2381442 | doi = 10.1056/NEJM199008303230904 }}</ref> The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by [[French Anderson]] in a trial starting in September 1990. It is thought to be able to cure many genetic disorders or treat them over time.

Between 1989 and December 2018, over 2,900 clinical trials were conducted, with more than half of them in [[Phases of clinical research|phase I]].<ref name="JGenMed Database">[http://www.abedia.com/wiley/phases.php Gene Therapy Clinical Trials Worldwide Database] {{Webarchive|url=https://web.archive.org/web/20200731222220/http://www.abedia.com/wiley/phases.php |date=31 July 2020 }}. ''The Journal of Gene Medicine''. Wiley (June 2016)</ref> As of 2017, Spark Therapeutics' [[Luxturna]] ([[Leber's congenital amaurosis|RPE65 mutation-induced blindness]]) and Novartis' [[Tisagenlecleucel|Kymriah]] ([[Chimeric antigen receptor T cell]] therapy) are the FDA's first approved gene therapies to enter the market. Since that time, [[Biopharmaceutical drug|drugs]] such as Novartis' [[Zolgensma]] and [[Alnylam]]'s [[Patisiran]] have also received FDA approval, in addition to other companies' gene therapy drugs. Most of these approaches utilize [[adeno-associated virus]]es (AAVs) and [[lentivirus]]es for performing gene insertions, ''[[in vivo]]'' and ''[[ex vivo]]'', respectively. AAVs are characterized by stabilizing the [[viral capsid]], lower immunogenicity, ability to [[Transduction (genetics)|transduce]] both dividing and nondividing cells, the potential to integrate site specifically and to achieve long-term expression in the in-vivo treatment. (Gorell et al. 2014) [[Allele-specific oligonucleotide|ASO]] / [[Small interfering RNA|siRNA]] approaches such as those conducted by [[Alnylam]] and [[Ionis Pharmaceuticals]] require non-viral delivery systems, and utilize alternative mechanisms for trafficking to liver cells by way of [[GalNAc]] transporters.

The concept of gene therapy is to fix a genetic problem at its source. If, for instance, a mutation in a certain gene causes the production of a dysfunctional protein resulting (usually recessively) in an inherited disease, gene therapy could be used to deliver a copy of this gene that does not contain the deleterious mutation and thereby produces a functional protein. This strategy is referred to as gene replacement therapy and is employed to treat inherited retinal diseases.<ref name="Maguire 2008" /><ref name="pmid24439297" />

While the concept of gene replacement therapy is mostly suitable for recessive diseases, novel strategies have been suggested that are capable of also treating conditions with a dominant pattern of inheritance.
* The introduction of [[CRISPR gene editing]] has opened new doors for its application and utilization in gene therapy, as instead of pure replacement of a gene, it enables correction of the particular genetic defect.<ref name="Bak 600–611">{{cite journal | vauthors = Bak RO, Gomez-Ospina N, Porteus MH | title = Gene Editing on Center Stage | journal = Trends in Genetics | volume = 34 | issue = 8 | pages = 600–611 | date = August 2018 | pmid = 29908711 | doi = 10.1016/j.tig.2018.05.004 | s2cid = 49269023 }}</ref> Solutions to medical hurdles, such as the eradication of latent human immunodeficiency virus ([[HIV]]) reservoirs and correction of the mutation that causes sickle cell disease, may be available as a therapeutic option in the future.<ref>{{cite journal | vauthors = Dever DP, Bak RO, Reinisch A, Camarena J, Washington G, Nicolas CE, Pavel-Dinu M, Saxena N, Wilkens AB, Mantri S, Uchida N, Hendel A, Narla A, Majeti R, Weinberg KI, Porteus MH | display-authors = 6 | title = CRISPR/Cas9 β-globin gene targeting in human haematopoietic stem cells | journal = Nature | volume = 539 | issue = 7629 | pages = 384–389 | date = November 2016 | pmid = 27820943 | pmc = 5898607 | doi = 10.1038/nature20134 | bibcode = 2016Natur.539..384D }}</ref><ref>{{cite journal | vauthors = Gupta RM, Musunuru K | title = Expanding the genetic editing tool kit: ZFNs, TALENs, and CRISPR-Cas9 | journal = The Journal of Clinical Investigation | volume = 124 | issue = 10 | pages = 4154–61 | date = October 2014 | pmid = 25271723 | pmc = 4191047 | doi = 10.1172/JCI72992 }}</ref><ref>{{cite journal | vauthors = Sanches-da-Silva GN, Medeiros LF, Lima FM | title = The Potential Use of the CRISPR-Cas System for HIV-1 Gene Therapy | journal = International Journal of Genomics | volume = 2019 | pages = 8458263 | date = 21 August 2019 | pmid = 31531340 | pmc = 6721108 | doi = 10.1155/2019/8458263 | doi-access = free }}</ref>
* Prosthetic gene therapy aims to enable cells of the body to take over functions they physiologically do not carry out. One example is the so-called vision restoration gene therapy, that aims to restore vision in patients with end-stage retinal diseases.<ref>Patent: US7824869B2</ref><ref>{{cite journal | vauthors = Bi A, Cui J, Ma YP, Olshevskaya E, Pu M, Dizhoor AM, Pan ZH | title = Ectopic expression of a microbial-type rhodopsin restores visual responses in mice with photoreceptor degeneration | journal = Neuron | volume = 50 | issue = 1 | pages = 23–33 | date = April 2006 | pmid = 16600853 | pmc = 1459045 | doi = 10.1016/j.neuron.2006.02.026 | doi-access=free }}</ref> In end-stage retinal diseases, the photoreceptors, as the primary light sensitive cells of the retina are irreversibly lost. By the means of prosthetic gene therapy light sensitive proteins are delivered into the remaining cells of the retina, to render them light sensitive and thereby enable them to signal visual information towards the brain.

Not all medical procedures that introduce alterations to a patient's genetic makeup can be considered gene therapy. [[Bone marrow transplantation]] and [[organ transplants]] in general have been found to introduce foreign DNA into patients.<ref>{{cite news|title=DNA Double Take| last = Zimmer | first = Carl | name-list-style = vanc | date = 16 September 2013|work=The New York Times|url=https://www.nytimes.com/2013/09/17/science/dna-double-take.html |archive-url=https://ghostarchive.org/archive/20220102/https://www.nytimes.com/2013/09/17/science/dna-double-take.html |archive-date=2 January 2022 |url-access=limited |url-status=live }}</ref>
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==Background==
Gene therapy was conceptualized in 1972, by authors who urged caution before commencing human gene therapy studies.

The first attempt, an unsuccessful one, at gene therapy (as well as the first case of medical transfer of foreign genes into humans not counting [[organ transplantation]]) was performed by [[Martin Cline]] on 10 July 1980.<ref>{{cite book | title = Human gene therapy – A background paper | author = U.S. Congress, Office of Technology Assessment | publisher = DIANE Publishing | isbn = 978-1-4289-2371-3 | url = https://books.google.com/books?id=FxGjBqEL-3kC&pg=PA45 | date = December 1984 }}</ref><ref>{{cite journal | vauthors = Sun M | title = Martin Cline loses appeal on NIH grant | journal = Science | volume = 218 | issue = 4567 | pages = 37 | date = October 1982 | pmid = 7123214 | doi = 10.1126/science.7123214 | bibcode = 1982Sci...218...37S }}</ref> Cline claimed that one of the genes in his patients was active six months later, though he never published this data or had it verified<ref>{{cite book | chapter-url = https://books.google.com/books?id=FzuwRwb--X4C&pg=PA30 | chapter = Gene Therapy for Neurological Disorders: New Therapies or Human Experimentation? | title = A Companion to Genethics | first = P.R. | last = Lowenstein | editor-first1 = Justine | editor-last1 = Burley | editor-first2 = John | editor-last2 = Harris | name-list-style = vanc | isbn = 978-0-470-75637-9 | publisher=John Wiley & Sons | year = 2008 }}</ref> and even if he is correct, it's unlikely it produced any significant beneficial effects treating [[beta thalassemia]].{{medcn|date=August 2020}}

After extensive research on animals throughout the 1980s and a 1989 bacterial gene tagging trial on humans, the first gene therapy widely accepted as a success was demonstrated in a trial that started on 14 September 1990, when Ashanthi DeSilva was treated for [[adenosine deaminase deficiency|ADA]]-[[severe combined immunodeficiency|SCID]].<ref name="Gene Therapy Finds Its Niche">{{cite journal | vauthors = Sheridan C | title = Gene therapy finds its niche | journal = Nature Biotechnology | volume = 29 | issue = 2 | pages = 121–128 | date = February 2011 | pmid = 21301435 | doi = 10.1038/nbt.1769 | s2cid = 5063701 }}</ref>

The first somatic treatment that produced a permanent genetic change was initiated in 1993.<ref>{{cite journal |vauthors=O'Malley BW, Ledley FD |title=Somatic gene therapy. Methods for the present and future |journal=Arch Otolaryngol Head Neck Surg |volume=119 |issue=10 |pages=1100–7 |date=October 1993 |pmid=8398061 |doi=10.1001/archotol.1993.01880220044007 }}</ref> The goal was to cure malignant brain tumors by using recombinant DNA to transfer a gene making the tumor cells sensitive to a drug that in turn would cause the tumor cells to die.<ref>{{cite journal | vauthors = Oldfield EH, Ram Z, Culver KW, Blaese RM, DeVroom HL, Anderson WF | title = Gene therapy for the treatment of brain tumors using intra-tumoral transduction with the thymidine kinase gene and intravenous ganciclovir | journal = Human Gene Therapy | volume = 4 | issue = 1 | pages = 39–69 | date = February 1993 | pmid = 8384892 | doi = 10.1089/hum.1993.4.1-39 }}</ref>

The polymers are either [[translation (biology)|translated]] into [[proteins]], interfere with target [[gene expression]], or possibly correct [[genetic mutations]]. The most common form uses [[DNA]] that encodes a functional, therapeutic [[gene]] to replace a [[mutate]]d gene. The polymer molecule is packaged within a "[[Vector (molecular biology)|vector]]", which carries the molecule inside cells.{{medcn|date=August 2020}}

Early clinical failures led to dismissals of gene therapy. Clinical successes since 2006 regained researchers' attention, although {{as of|2014|lc=y}}, it was still largely an experimental technique.<ref name="Richards2012" /> These include treatment of [[retinal diseases]] [[Leber's congenital amaurosis]]<ref name="Maguire 2008" /><ref name="Simonelli 2010" /><ref name="Cideciyan 2009" /><ref name="Bainbridge 2008" /> and [[choroideremia]],<ref name="BBC2016">{{cite news|last1=Ghosh|first1=Pallab | name-list-style = vanc |title=Gene therapy reverses sight loss and is long-lasting|url=https://www.bbc.co.uk/news/science-environment-36101786|access-date=29 April 2016|publisher=BBC News Online |date=28 April 2016 }}</ref> [[x-linked severe combined immunodeficiency|X-linked SCID]],<ref>{{cite journal | vauthors = Fischer A, Hacein-Bey-Abina S, Cavazzana-Calvo M | title = 20 years of gene therapy for SCID | journal = Nature Immunology | volume = 11 | issue = 6 | pages = 457–460 | date = June 2010 | pmid = 20485269 | doi = 10.1038/ni0610-457 | s2cid = 11300348 }}</ref> ADA-SCID,<ref>{{cite journal | vauthors = Ferrua F, Brigida I, Aiuti A | title = Update on gene therapy for adenosine deaminase-deficient severe combined immunodeficiency | journal = Current Opinion in Allergy and Clinical Immunology | volume = 10 | issue = 6 | pages = 551–556 | date = December 2010 | pmid = 20966749 | doi = 10.1097/ACI.0b013e32833fea85 | s2cid = 205435278 }}</ref><ref name="NewScientist1013" /> [[adrenoleukodystrophy]],<ref>{{cite journal | vauthors = Cartier N, Aubourg P | title = Hematopoietic stem cell transplantation and hematopoietic stem cell gene therapy in X-linked adrenoleukodystrophy | journal = Brain Pathology | volume = 20 | issue = 4 | pages = 857–862 | date = July 2010 | pmid = 20626747 | doi = 10.1111/j.1750-3639.2010.00394.x | s2cid = 24182017 | pmc = 8094635 }}</ref> [[chronic lymphocytic leukemia]] (CLL),<ref name="Porter" /> [[acute lymphocytic leukemia]] (ALL),<ref name="SloanKettering" /> [[multiple myeloma]],<ref name="Adaptimmune">{{cite magazine | last = Coghlan | first = Andy | name-list-style = vanc | date = 11 December 2013 | url = https://www.newscientist.com/article/dn22613-soupedup-immune-cells-force-leukaemia-into-remission.html | title = Souped-up immune cells force leukaemia into remission | magazine = New Scientist | access-date = 15 April 2013 }}</ref> [[haemophilia]],<ref name="NewScientist1013" /> and [[Parkinson's disease]].<ref>{{cite journal | vauthors = LeWitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AW, Eskandar EN, Kostyk SK, Thomas K, Sarkar A, Siddiqui MS, Tatter SB, Schwalb JM, Poston KL, Henderson JM, Kurlan RM, Richard IH, Van Meter L, Sapan CV, During MJ, Kaplitt MG, Feigin A | display-authors = 6 | title = AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial | journal = The Lancet. Neurology | volume = 10 | issue = 4 | pages = 309–319 | date = April 2011 | pmid = 21419704 | doi = 10.1016/S1474-4422(11)70039-4 | s2cid = 37154043 }}</ref> Between 2013 and April 2014, US companies invested over $600 million in the field.<ref name="Forbes">{{cite web | last = Herper | first = Matthew | name-list-style = vanc | date = 26 March 2014 | url = https://www.forbes.com/sites/matthewherper/2014/03/26/once-seen-as-too-scary-editing-peoples-genes-with-viruses-makes-a-618-million-comeback/ | title = Gene Therapy's Big Comeback | work = Forbes | access-date = 28 April 2014 }}</ref>

The first commercial gene therapy, [[Gendicine]], was approved in China in 2003, for the treatment of certain cancers.<ref name="Gend">{{cite journal | vauthors = Pearson S, Jia H, Kandachi K | title = China approves first gene therapy | journal = Nature Biotechnology | volume = 22 | issue = 1 | pages = 3–4 | date = January 2004 | pmid = 14704685 | doi = 10.1038/nbt0104-3 | pmc = 7097065 }}</ref> In 2011, [[Neovasculgen]] was registered in Russia as the first-in-class gene-therapy drug for treatment of [[peripheral artery disease]], including [[critical limb ischemia]].<ref name="Neuvasculgen">{{cite news|title=Gene Therapy for PAD Approved|url=http://www.dddmag.com/news/2011/12/gene-therapy-pad-approved|access-date=5 August 2015|date=6 December 2011}}</ref>
In 2012, [[Glybera]], a treatment for a rare [[inherited disorder]], [[lipoprotein lipase deficiency]], became the first treatment to be approved for clinical use in either Europe or the United States after its endorsement by the [[European Commission]].<ref name="Richards2012" /><ref name="Gallagher" />

Following early advances in [[genetic engineering]] of bacteria, cells, and small animals, scientists started considering how to apply it to medicine. Two main approaches were considered – replacing or disrupting defective genes.<ref>{{cite web | title=What is gene therapy? | website=Genetics Home Reference | date=28 March 2016 | url=https://ghr.nlm.nih.gov/handbook/therapy/genetherapy | archive-url=https://web.archive.org/web/20160406021547/https://ghr.nlm.nih.gov/handbook/therapy/genetherapy | archive-date=6 April 2016 | url-status=dead | access-date=2 January 2022}}</ref> Scientists focused on diseases caused by single-gene defects, such as [[cystic fibrosis]], haemophilia, [[muscular dystrophy]], [[thalassemia]], and [[sickle cell anemia]]. [[Glybera]] treats one such disease, caused by a defect in [[lipoprotein lipase]].<ref name="Gallagher" />

DNA must be administered, reach the damaged cells, enter the cell and either express or disrupt a protein.<ref>U.S. National Library of Medicine, Genomics Home Reference. [http://ghr.nlm.nih.gov/handbook/therapy/procedures How does gene therapy work?]</ref> Multiple delivery techniques have been explored. The initial approach incorporated DNA into an engineered [[virus]] to deliver the DNA into a [[chromosome]].<ref name="pmid23015375">{{cite journal | vauthors = Pezzoli D, Chiesa R, De Nardo L, Candiani G | title = We still have a long way to go to effectively deliver genes! | journal = Journal of Applied Biomaterials & Functional Materials | volume = 10 | issue = 2 | pages = 82–91 | date = September 2012 | pmid = 23015375 | doi = 10.5301/JABFM.2012.9707 | s2cid = 6283455 }}</ref><ref name="pmid23435812">{{cite journal | vauthors = Vannucci L, Lai M, Chiuppesi F, Ceccherini-Nelli L, Pistello M | title = Viral vectors: a look back and ahead on gene transfer technology | journal = The New Microbiologica | volume = 36 | issue = 1 | pages = 1–22 | date = January 2013 | pmid = 23435812 }}</ref> [[Naked DNA]] approaches have also been explored, especially in the context of [[vaccine]] development.<ref name="pmid23111168">{{cite journal | vauthors = Gothelf A, Gehl J | title = What you always needed to know about electroporation based DNA vaccines | journal = Human Vaccines & Immunotherapeutics | volume = 8 | issue = 11 | pages = 1694–1702 | date = November 2012 | pmid = 23111168 | pmc = 3601144 | doi = 10.4161/hv.22062 }}</ref>

Generally, efforts focused on administering a gene that causes a needed protein to be expressed. More recently, increased understanding of [[nucleases|nuclease]] function has led to more direct DNA editing, using techniques such as [[zinc finger nucleases]] and [[CRISPR]]. The vector incorporates genes into chromosomes. The expressed nucleases then knock out and replace genes in the chromosome. {{as of|2014}} these approaches involve removing cells from patients, editing a chromosome and returning the transformed cells to patients.<ref name="pmid20717154">{{cite journal | vauthors = Urnov FD, Rebar EJ, Holmes MC, Zhang HS, Gregory PD | title = Genome editing with engineered zinc finger nucleases | journal = Nature Reviews Genetics | volume = 11 | issue = 9 | pages = 636–646 | date = September 2010 | pmid = 20717154 | doi = 10.1038/nrg2842 | s2cid = 205484701 }}</ref>

[[Genome editing|Gene editing]] is a potential approach to alter the human genome to treat genetic diseases,<ref name="Bak 600–611"/> viral diseases,<ref>{{cite journal | vauthors = Stone D, Niyonzima N, Jerome KR | title = Genome editing and the next generation of antiviral therapy | journal = Human Genetics | volume = 135 | issue = 9 | pages = 1071–82 | date = September 2016 | pmid = 27272125 | pmc = 5002242 | doi = 10.1007/s00439-016-1686-2 }}</ref> and cancer.<ref>{{cite journal | vauthors = Cross D, Burmester JK | title = Gene therapy for cancer treatment: past, present and future | journal = Clinical Medicine & Research | volume = 4 | issue = 3 | pages = 218–27 | date = September 2006 | pmid = 16988102 | pmc = 1570487 | doi = 10.3121/cmr.4.3.218 }}</ref><ref>{{cite journal | vauthors = Maeder ML, Gersbach CA | title = Genome-editing Technologies for Gene and Cell Therapy | journal = Molecular Therapy | volume = 24 | issue = 3 | pages = 430–46 | date = March 2016 | pmid = 26755333 | pmc = 4786923 | doi = 10.1038/mt.2016.10 }}</ref> {{as of|2020}} these approaches are being studied in clinical trials.<ref>{{cite web|date=7 February 2019|title=Tests suggest scientists achieved 1st 'in body' gene editing|url=https://apnews.com/article/d728f86d70d94ce68dd4fedffe58d03f|access-date=17 November 2020|website=AP NEWS}}</ref><ref>{{cite journal|date=1 April 2020|title=First CRISPR therapy dosed|journal=Nature Biotechnology|volume=38|issue=4|pages=382|doi=10.1038/s41587-020-0493-4|pmid=32265555|s2cid=215406440|issn=1546-1696|doi-access=free}}</ref>

[[File:CRISPR-Cas9 mode of action.png|thumb|A duplex of crRNA and [[Trans-activating crRNA|tracrRNA]] acts as guide RNA to introduce a specifically located gene modification based on the RNA 5' upstream of the crRNA. Cas9 binds the tracrRNA and needs a DNA binding sequence (5'NGG3'), which is called protospacer adjacent motif (PAM). After binding, Cas9 introduces a DNA double strand break, which is then followed by gene modification via homologous recombination (HDR) or non-homologous end joining (NHEJ).]]

==Cell types==
Gene therapy may be classified into two types:

===Somatic===
In [[somatic cell]] gene therapy (SCGT), the therapeutic genes are transferred into any cell other than a [[gamete]], [[germ cell]], [[gametocyte]], or undifferentiated [[stem cell]]. Any such modifications affect the individual patient only, and are not inherited by [[offspring]]. Somatic gene therapy represents mainstream basic and clinical research, in which therapeutic DNA (either integrated in the [[genome]] or as an external [[episome]] or [[plasmid]]) is used to treat disease.<ref>{{cite journal | vauthors = Williams DA, Orkin SH | title = Somatic gene therapy. Current status and future prospects | journal = The Journal of Clinical Investigation | volume = 77 | issue = 4 | pages = 1053–6 | date = April 1986 | pmid = 3514670 | pmc = 424438 | doi = 10.1172/JCI112403 }}</ref>

Over 600 [[clinical trials]] utilizing SCGT are underway{{when|date=July 2018}} in the US. Most focus on severe genetic disorders, including [[Primary immunodeficiency|immunodeficiencies]], [[haemophilia]], [[Thalassemia|thalassaemia]], and [[cystic fibrosis]]. Such single gene disorders are good candidates for somatic cell therapy. The complete correction of a genetic disorder or the replacement of multiple genes is not yet possible. Only a few of the trials are in the advanced stages.<ref name="somatic">{{cite journal | vauthors = Mavilio F, Ferrari G | title = Genetic modification of somatic stem cells. The progress, problems and prospects of a new therapeutic technology | journal = EMBO Reports | volume = 9 Suppl 1 | pages = S64–69 | date = July 2008 | issue = Suppl 1 | pmid = 18578029 | pmc = 3327547 | doi = 10.1038/embor.2008.81 }}</ref>{{update inline|date=November 2018}}

===Germline===
In [[germline]] gene therapy (GGT), [[germ cell]]s ([[sperm]] or [[egg cell]]s) are modified by the introduction of functional genes into their genomes. Modifying a germ cell causes all the organism's cells to contain the modified gene. The change is therefore [[heritable]] and passed on to later generations. Australia, Canada, Germany, Israel, Switzerland, and the Netherlands<ref name="JHU">{{cite web|url=http://www.dnapolicy.org/policy.international.php?action=detail&laws_id=38 |title=International Law |year=2010 |publisher=The Genetics and Public Policy Center, Johns Hopkins University Berman Institute of Bioethics |url-status=dead |archive-url=https://web.archive.org/web/20140902072742/http://www.dnapolicy.org/policy.international.php?action=detail&laws_id=38 |archive-date=2 September 2014 }}</ref> prohibit GGT for application in human beings, for technical and ethical reasons, including insufficient knowledge about possible risks to future generations<ref name="JHU" /> and higher risks versus SCGT.<ref>{{cite book | vauthors = Strachnan T, Read AP | year = 2004 | title = Human Molecular Genetics | edition = 3rd | publisher = Garland Publishing | page = [https://archive.org/details/humanmolecularge0000stra_b0q6/page/616 616] | isbn = 978-0-8153-4184-0 | url = https://archive.org/details/humanmolecularge0000stra_b0q6/page/616 }}</ref> The US has no federal controls specifically addressing human genetic modification (beyond FDA regulations for therapies in general).<ref name="JHU" /><ref name="germline">{{cite web | vauthors = Hanna K | year = 2006 |title=Germline Gene Transfer|publisher=National Human Genome Research Institute|url=http://www.genome.gov/10004764}}</ref><ref name="somatic2">{{cite web|year=2013|title=Human Cloning and Genetic Modification|publisher=Association of Reproductive Health Officials|url=http://www.arhp.org/publications-and-resources/patient-resources/printed-materials/cloning|archive-url=https://web.archive.org/web/20130618193943/http://www.arhp.org/Publications-and-Resources/Patient-Resources/printed-materials/Cloning|archive-date=18 June 2013}}</ref><ref name="germline2">{{cite web|url=http://www.ama-assn.org/ama/pub/physician-resources/medical-science/genetics-molecular-medicine/current-topics/gene-therapy.page|title=Gene Therapy|date=4 April 2014|work=ama-assn.org|access-date=22 March 2015}}</ref>

==Vectors==
{{Main|Vectors in gene therapy}}

The delivery of DNA into cells can be accomplished by multiple [[Vectors in Gene Therapy|methods]]. The two major classes are [[recombinant virus]]es (sometimes called biological nanoparticles or viral vectors) and [[naked DNA]] or DNA complexes (non-viral methods).<ref>{{cite journal|last1=Nayerossadat|first1=Nouri|last2=Ali|first2=PalizbanAbas|last3=Maedeh|first3=Talebi|date=2012|title=Viral and nonviral delivery systems for gene delivery|journal=Advanced Biomedical Research|volume=1|issue=1|pages=27|doi=10.4103/2277-9175.98152|pmid=23210086|issn=2277-9175|pmc=3507026 | name-list-style = vanc }}</ref>

===Viruses===
{{Main|Viral vector|Lentiviral vector in gene therapy}}
{{unreferenced section|date=December 2022}}
In order to [[Viral replication|replicate]], [[virus]]es introduce their genetic material into the host cell, tricking the host's cellular machinery into using it as blueprints for viral proteins. [[Retrovirus]]es go a stage further by having their genetic material copied into the genome of the host cell. Scientists exploit this by substituting a virus's genetic material with therapeutic DNA or RNA. A number of viruses have been used for human gene therapy, including retroviruses, [[adenovirus]]es, [[herpes simplex virus|herpes simplex]], [[vaccinia virus|vaccinia]], and [[adeno-associated virus]].<ref name="JGenMed Database" /> Like the genetic material (DNA or RNA) in viruses, therapeutic DNA can be designed to simply serve as a temporary blueprint that is degraded naturally or (at least theoretically) to enter the host's genome, becoming a permanent part of the host's DNA in infected cells.

=== Non-viral ===
{{More citations needed section|date=April 2021}}
Non-viral vectors for gene therapy<ref>{{cite journal |last1=Yin |first1=Hao |last2=Kanasty |first2=Rosemary L. |last3=Eltoukhy |first3=Ahmed A. |last4=Vegas |first4=Arturo J. |last5=Dorkin |first5=J. Robert |last6=Anderson |first6=Daniel G. |title=Non-viral vectors for gene-based therapy |journal=Nature Reviews Genetics |date=August 2014 |volume=15 |issue=8 |pages=541–555 |doi=10.1038/nrg3763|pmid=25022906 |s2cid=15273455 | name-list-style = vanc }}</ref> present certain advantages over viral methods, such as large scale production and low host [[immunogenicity]]. However, non-viral methods initially produced lower levels of [[transfection]] and [[gene expression]], and thus lower therapeutic efficacy. Newer technologies offer promise of solving these problems, with the advent of increased cell-specific targeting and subcellular trafficking control.

[[Vectors in Gene Therapy#Non-viral methods|Methods for non-viral gene therapy]] include the injection of naked DNA, [[electroporation]], the [[gene gun]], [[sonoporation]], [[magnetofection]], the use of [[oligonucleotide]]s, lipoplexes, dendrimers, and inorganic nanoparticles.

More recent approaches, such as those performed by companies such as [[Ligandal]], offer the possibility of creating cell-specific targeting technologies for a variety of gene therapy modalities, including RNA, DNA and gene editing tools such as CRISPR. Other companies, such as [[Arbutus Biopharma]] and [[Arcturus Therapeutics]], offer non-viral, non-cell-targeted approaches that mainly exhibit liver trophism. In more recent years, startups such as [[Sixfold Bio]], [[GenEdit]], and [[Spotlight Therapeutics]] have begun to solve the non-viral gene delivery problem. Non-viral techniques offer the possibility of repeat dosing and greater tailorability of genetic payloads, which in the future will be more likely to take over viral-based delivery systems.

Companies such as [[Editas Medicine]], [[Intellia Therapeutics]], [[CRISPR Therapeutics]], [[Casebia]], [[Cellectis]], [[Precision Biosciences]], [[bluebird bio]], and [[Sangamo]] have developed non-viral gene editing techniques, however frequently still use viruses for delivering gene insertion material following genomic cleavage by guided [[nuclease]]s. These companies focus on gene editing, and still face major delivery hurdles.

[[BioNTech]], [[Moderna Therapeutics]] and [[CureVac]] focus on delivery of [[mRNA]] payloads, which are necessarily non-viral delivery problems.

[[Alnylam]], [[Dicerna Pharmaceuticals]], and [[Ionis Pharmaceuticals]] focus on delivery of [[siRNA]] (antisense oligonucleotides) for gene suppression, which also necessitate non-viral delivery systems.

In academic contexts, a number of laboratories are working on delivery of [[Polyethylene glycol|PEG]]ylated particles, which form serum protein coronas and chiefly exhibit [[LDL receptor]] mediated uptake in cells ''in vivo''.<ref>{{cite journal | vauthors = Bertrand N, Grenier P, Mahmoudi M, Lima EM, Appel EA, Dormont F, Lim JM, Karnik R, Langer R, Farokhzad OC | display-authors = 6 | title = Mechanistic understanding of in vivo protein corona formation on polymeric nanoparticles and impact on pharmacokinetics | journal = Nature Communications | volume = 8 | issue = 1 | pages = 777 | date = October 2017 | pmid = 28974673 | pmc = 5626760 | doi = 10.1038/s41467-017-00600-w | bibcode = 2017NatCo...8..777B }}</ref>

=== In vivo versus ex vivo therapies ===
In [[in vivo]] gene therapy, a vector (typically, a virus) is introduced to the patient, which then achieves the desired biological effect by passing the genetic material (e.g. for a missing protein) into the patient's cells. In [[ex vivo]] gene therapies, such as [[Chimeric antigen receptor T cell|CAR-T]] therapeutics, the patient's own cells (autologous) or healthy donor cells (allogeneic) are modified outside the body (hence, ex vivo) using a vector to express a particular protein, such as a chimeric antigen receptor.<ref>{{cite web|title=Gene & Cell Therapy FAQs {{!}} ASGCT - American Society of Gene & Cell Therapy {{!}} ASGCT - American Society of Gene & Cell Therapy|url=https://asgct.org/education/more-resources/gene-and-cell-therapy-faqs|access-date=23 July 2021|website=asgct.org}}</ref>

In vivo gene therapy is seen as simpler, since it does not require the harvesting of [[Mitosis|mitotic]] cells. However, ex vivo gene therapies are better tolerated and less associated with severe immune responses.<ref>{{cite web|title=Evaluation of the Clinical Success of Ex Vivo and In Vivo Gene Therapy|url=https://www.jyi.org/2009-january/2017/10/2/evaluation-of-the-clinical-success-of-ex-vivo-and-in-vivo-gene-therapy|access-date=23 July 2021|website=Journal of Young Investigators}}</ref> The death of [[Jesse Gelsinger]] in a trial of an [[Adenoviridae|adenovirus]]-vectored treatment for [[ornithine transcarbamylase deficiency]] due to a systemic inflammatory reaction led to a temporary halt on gene therapy trials across the United States.<ref>{{cite web|title=Challenges In Gene Therapy|url=https://learn.genetics.utah.edu/content/genetherapy/challenges/|access-date=23 July 2021|website=learn.genetics.utah.edu}}</ref> {{As of|2021}}, in vivo and ex vivo therapeutics are both seen as safe.<ref>{{cite journal|last=Mullard|first=Asher|date=15 May 2020|title=Gene-editing pipeline takes off|journal=Nature Reviews Drug Discovery|volume=19|issue=6|pages=367–372|doi=10.1038/d41573-020-00096-y|pmid=32415249|s2cid=218657910}}</ref>

==Gene doping==
{{Main|Gene doping}}

Athletes may adopt gene therapy technologies to improve their performance.<ref name="Gene Doping">{{cite web|title=WADA Gene Doping|url=http://www.wada-ama.org/en/Science-Medicine/Science-topics/Gene-Doping/|url-status=dead|archive-url=https://web.archive.org/web/20091121094012/http://www.wada-ama.org/en/Science-Medicine/Science-topics/Gene-Doping/|archive-date=21 November 2009|access-date=27 September 2013|publisher=WADA}}</ref> [[Gene doping]] is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could [[Level playing field|level the playing field]] if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.<ref>{{cite journal|vauthors=Kayser B, Mauron A, Miah A|date=March 2007|title=Current anti-doping policy: a critical appraisal|journal=BMC Medical Ethics|volume=8|pages=2|doi=10.1186/1472-6939-8-2|pmc=1851967|pmid=17394662}}</ref>



{{see|Human genetic enhancement}}
{{see also|Human germline engineering|Assisted reproductive technology}}
Genetic engineering could be used to cure diseases, but also to change physical appearance, [[metabolism]], and even [[Human enhancement|improve]] physical capabilities and mental faculties such as [[memory]] and [[intelligence]]. Ethical claims about germline engineering include beliefs that every [[fetus]] has a right to remain genetically unmodified, that parents hold the right to genetically modify their offspring, and that every child has the right to be born free of preventable diseases.<ref name="Evolution">{{cite journal|vauthors=Powell R, Buchanan A|date=February 2011|title=Breaking evolution's chains: the prospect of deliberate genetic modification in humans|journal=The Journal of Medicine and Philosophy|volume=36|issue=1|pages=6–27|doi=10.1093/jmp/jhq057|pmid=21228084}}</ref><ref name="Baylis, Francoise 2004">{{cite journal|vauthors=Baylis F, Robert JS|year=2004|title=The inevitability of genetic enhancement technologies|journal=Bioethics|volume=18|issue=1|pages=1–26|doi=10.1111/j.1467-8519.2004.00376.x|pmid=15168695}}</ref><ref>{{cite book|last=Evans|first=John|title=Playing God?: Human Genetic Engineering and the Rationalization of Public Bioethical Debate|publisher=University of Chicago Press|year=2002|isbn=978-0-226-22262-2|name-list-style=vanc}}</ref> For parents, genetic engineering could be seen as another child enhancement technique to add to diet, exercise, education, training, cosmetics, and plastic surgery.<ref name="Enhancement">{{cite web | title=The Center for Health Ethics - University of Missouri School of Medicine - Gene Therapy and Genetic Engineering | website=ethics.missouri.edu | date=3 December 2013 | url=https://ethics.missouri.edu/Gene-Therapy.aspx | archive-url=https://web.archive.org/web/20131203040308/https://ethics.missouri.edu/Gene-Therapy.aspx | archive-date=3 December 2013 | url-status=dead | access-date=2 January 2022}}</ref><ref name="Roco_Bainbridge_2002">{{cite journal|vauthors=Roco MC, Bainbridge WS|year=2002|title=Converging Technologies for Improving Human Performance: Integrating From the Nanoscale|journal=Journal of Nanoparticle Research|volume=4|issue=4|pages=281–295|bibcode=2002JNR.....4..281R|doi=10.1023/A:1021152023349|s2cid=136290217}}</ref> Another theorist claims that moral concerns limit but do not prohibit germline engineering.<ref>{{cite journal|vauthors=Allhoff F|date=March 2005|title=Germ-line genetic enhancement and Rawlsian primary goods|url=http://jetpress.org/v18/allhoff.pdf |archive-url=https://web.archive.org/web/20120130182802/http://jetpress.org/v18/allhoff.pdf |archive-date=30 January 2012 |url-status=live|journal=Kennedy Institute of Ethics Journal|volume=15|issue=1|pages=39–56|citeseerx=10.1.1.566.171|doi=10.1353/ken.2005.0007|pmid=15881795|s2cid=14432440}}</ref>

A recent issue of the journal ''Bioethics'' was devoted to moral issues surrounding germline genetic engineering in people.<ref>{{cite journal|vauthors=Ranisch R|date=January 2020|title=Special Issue:Human Germline Editing|url=https://onlinelibrary.wiley.com/toc/14678519/2020/34/1|journal=Bioethics|volume=34|issue=1|pages=1–143}}</ref>

Possible regulatory schemes include a complete ban, provision to everyone, or professional self-regulation. The [[American Medical Association]]'s Council on Ethical and Judicial Affairs stated that "genetic interventions to enhance traits should be considered permissible only in severely restricted situations: (1) clear and meaningful benefits to the fetus or child; (2) no trade-off with other characteristics or traits; and (3) equal access to the genetic technology, irrespective of income or other socioeconomic characteristics."<ref>{{cite journal|date=July 1994|title=Ethical issues related to prenatal genetic testing. The Council on Ethical and Judicial Affairs, American Medical Association|journal=Archives of Family Medicine|volume=3|issue=7|pages=633–642|doi=10.1001/archfami.3.7.633|pmid=7921302}}</ref>

As early in the history of [[biotechnology]] as 1990, there have been scientists opposed to attempts to modify the human [[germline]] using these new tools,<ref>[https://web.archive.org/web/20010805085535/http://www.cioms.ch/frame_1990_texts_of_guidelines.htm The Declaration of Inuyama: Human Genome Mapping, Genetic Screening and Gene Therapy]. cioms.ch</ref> and such concerns have continued as technology progressed.<ref>{{cite journal|vauthors=Smith KR, Chan S, Harris J|date=October 2012|title=Human germline genetic modification: scientific and bioethical perspectives|journal=Archives of Medical Research|volume=43|issue=7|pages=491–513|doi=10.1016/j.arcmed.2012.09.003|pmid=23072719}}</ref><ref>{{cite journal|last1=Reardon|first1=Sara|date=14 February 2017|title=US science advisers outline path to genetically modified babies|url=http://www.nature.com/news/us-science-advisers-outline-path-to-genetically-modified-babies-1.21474|journal=Nature|doi=10.1038/nature.2017.21474|doi-access=free|name-list-style=vanc}}</ref> With the advent of new techniques like [[CRISPR]], in March 2015 a group of scientists urged a worldwide moratorium on clinical use of gene editing technologies to edit the [[human genome]] in a way that can be inherited.<ref name="NYT-20150319" /><ref name="NYT-20150303-AP" /><ref name="SCI-20150319" /><ref name="NAT-20150312" /> In April 2015, researchers sparked controversy when they [[CRISPR#Society and culture|reported]] results of [[basic research]] to edit the [[DNA]] of non-viable [[human embryos]] using CRISPR.<ref name="PC-20150418">{{cite journal|vauthors=Liang P, Xu Y, Zhang X, Ding C, Huang R, Zhang Z, Lv J, Xie X, Chen Y, Li Y, Sun Y, Bai Y, Songyang Z, Ma W, Zhou C, Huang J | display-authors=6 |date=May 2015|title=CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes|journal=Protein & Cell|volume=6|issue=5|pages=363–372|doi=10.1007/s13238-015-0153-5|pmc=4417674|pmid=25894090}}</ref><ref name="NYT-20150423">{{cite news|last=Kolata|first=Gina|date=23 April 2015|title=Chinese Scientists Edit Genes of Human Embryos, Raising Concerns|work=[[The New York Times]]|url=https://www.nytimes.com/2015/04/24/health/chinese-scientists-edit-genes-of-human-embryos-raising-concerns.html |archive-url=https://ghostarchive.org/archive/20220102/https://www.nytimes.com/2015/04/24/health/chinese-scientists-edit-genes-of-human-embryos-raising-concerns.html |archive-date=2 January 2022 |url-access=limited |url-status=live|access-date=24 April 2015|name-list-style=vanc}}{{cbignore}}</ref> A committee of the American [[National Academy of Sciences]] and [[National Academy of Medicine]] gave qualified support to human genome editing in 2017<ref>{{cite news|last=Harmon|first=Amy|date=14 February 2017|title=Human Gene Editing Receives Science Panel's Support|newspaper=The New York Times|url=https://www.nytimes.com/2017/02/14/health/human-gene-editing-panel.html |archive-url=https://ghostarchive.org/archive/20220102/https://www.nytimes.com/2017/02/14/health/human-gene-editing-panel.html |archive-date=2 January 2022 |url-access=limited |url-status=live|access-date=17 February 2017|issn=0362-4331|name-list-style=vanc}}{{cbignore}}</ref><ref>{{cite web|last1=Committee on Human Gene Editing: Scientific, Medical, and Ethical Considerations|title=Human Genome Editing: Science, Ethics, and Governance|url=http://nationalacademies.org/gene-editing/consensus-study/index.htm|access-date=21 February 2017|website=nationalacademies.org|publisher=National Academy of Sciences; National Academy of Medicine | name-list-style = vanc }}</ref> once answers have been found to safety and efficiency problems "but only for serious conditions under stringent oversight."<ref>{{cite web|date=14 February 2017|title=Scientists OK genetically engineering babies|url=https://nypost.com/2017/02/14/scientists-ok-genetically-engineering-babies/|access-date=17 February 2017|website=New York Post|publisher=Reuters}}</ref>

== Treatment of genetic diseases ==
Gene therapy approaches to replace a faulty gene with a healthy gene have been proposed and are being studied for treating some genetic diseases. Diseases such as [[sickle cell disease]] that are caused by [[autosomal recessive disorder]]s for which a person's normal [[phenotype]] or cell function may be restored in cells that have the disease by a normal copy of the gene that is mutated, may be a good candidate for gene therapy treatment.<ref name="pmid 28696921">{{cite journal|date=September 2017|title=ASPsiRNA: A Resource of ASP-siRNAs Having Therapeutic Potential for Human Genetic Disorders and Algorithm for Prediction of Their Inhibitory Efficacy|journal=G3|volume=7|issue=9|pages=2931–2943|doi=10.1534/g3.117.044024|pmid=28696921|doi-access=free|last1=Monga|first1=Isha|last2=Qureshi|first2=Abid|last3=Thakur|first3=Nishant|last4=Gupta|first4=Amit Kumar|last5=Kumar|first5=Manoj|pmc=5592921 | name-list-style = vanc }}</ref><ref name=":0">{{cite journal|last1=Olowoyeye|first1=Abiola|last2=Okwundu|first2=Charles I.|date=November 2020|title=Gene therapy for sickle cell disease|journal=The Cochrane Database of Systematic Reviews|volume=2020|issue=11|pages=CD007652|doi=10.1002/14651858.CD007652.pub7|issn=1469-493X|pmid=33251574|pmc=8275984 | name-list-style = vanc }}</ref> The risks and benefits related to gene therapy for sickle cell disease are not known.<ref name=":0" />

===List of gene therapies for treatment of disease===
{{See also|List of gene therapies}}

Some genetic therapies have been approved by the U.S. [[Food and Drug Administration]] (FDA), the [[European Medicines Agency]] (EMA), and for use in Russia and China.
{| class="sortable wikitable"
|+List of approved gene therapies for the treatment of disease
!INN
!Brand name
!Type
!Manufacturer
!Target
![[FDA]] approved
![[European Medicines Agency|EMA]] authorized
|-
|[[alipogene tiparvovec]]
|Glybera
|In vivo
|[[Chiesi Farmaceutici]]
|[[lipoprotein lipase deficiency]]
|No
|Withdrawn
|-
|[[atidarsagene autotemcel]]
|Libmeldy
([[Arylsulfatase A]] gene encoding autologous [[CD34|CD34+]] cells)
|Ex vitro
|[[Orchard Therapeutics]]
|[[metachromatic leukodystrophy]]
|No
|17 December 2020<ref>{{cite press release|date=21 December 2020|title=Orchard Therapeutics Receives EC Approval for Libmeldy for the Treatment of Early-Onset Metachromatic Leukodystrophy (MLD)|url=https://www.globenewswire.com/news-release/2020/12/21/2148486/0/en/Orchard-Therapeutics-Receives-EC-Approval-for-Libmeldy-for-the-Treatment-of-Early-Onset-Metachromatic-Leukodystrophy-MLD.html|access-date=23 July 2021|publisher=Orchard Therapeutics | via=GlobeNewswire}}</ref>
|-
|[[Strimvelis|autologous CD34+]]
|Strimvelis
|
|
|adenosine deaminase deficiency (ADA-SCID)
|
|26 May 2016
|-
|[[axicabtagene ciloleucel]]
|Yescarta
|
|
|large B-cell lymphoma
|18 October 2017
|23 August 2018
|-
|[[betibeglogene autotemcel]]
|Zynteglo
|
|
|beta thalassemia
|17 August 2022<ref>{{Cite web |last=Commissioner |first=Office of the |date=17 August 2022 |title=FDA Approves First Cell-Based Gene Therapy to Treat Adult and Pediatric Patients with Beta-thalassemia Who Require Regular Blood Transfusions |url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-treat-adult-and-pediatric-patients-beta-thalassemia-who |access-date=31 August 2022 |website=FDA |language=en}}</ref>
|29 May 2019
|-
|[[brexucabtagene autoleucel]]
|Tecartus
|Ex vitro
|[[Kite Pharma]]
|[[mantle cell lymphoma]] and [[acute lymphoblastic leukemia]]
|24 July 2020<ref name="FDA PR">{{cite press release | title=FDA Approves First Cell-Based Gene Therapy For Adult Patients with Relapsed or Refractory MCL | website=U.S. [[Food and Drug Administration]] (FDA) | date=24 July 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-adult-patients-relapsed-or-refractory-mcl | access-date=24 July 2020}}</ref><ref name="FDA 20210101">{{cite web | title=FDA approves brexucabtagene autoleucel for relapsed or refractory B-cell precursor acute lymphoblastic leukemia | website=U.S. [[Food and Drug Administration]] (FDA) | date=1 October 2021 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-b-cell-precursor-acute-lymphoblastic | access-date=2 October 2021}}</ref>
|14 December 2020<ref>{{cite web|title=Tecartus|url=https://www.ema.europa.eu/en/medicines/human/EPAR/tecartus|website=[[European Medicines Agency]]}}</ref>
|-
|[[cambiogenplasmid]]
|Neovasculgen
|
|
|vascular endothelial growth factor peripheral artery disease
|
|
|-
|[[elivaldogene autotemcel]]
|Skysona
|
|
|cerebral adrenoleukodystrophy
|
|16 July 2021
|-
|[[gendicine]]
|
|
|
|head and neck squamous cell carcinoma
|
|
|-
|[[idecabtagene vicleucel]]
|Abecma
|Ex vivo
|[[Celgene]]
|[[multiple myeloma]]
|26 March 2021<ref>{{cite web|date=21 April 2021|title=Abecma (idecabtagene vicleucel)|url=https://www.fda.gov/vaccines-blood-biologics/abecma-idecabtagene-vicleucel|publisher=U.S. [[Food and Drug Administration]] (FDA)}}</ref>
|No
|-
|[[lisocabtagene maraleucel]]
|Breyanzi
|Ex vivo
|[[Juno Therapeutics]]
|[[B-cell lymphoma]]
|5 February 2021<ref>{{cite web|date=4 March 2021|title=Breyanzi (lisocabtagene maraleucel)|url=https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/breyanzi-lisocabtagene-maraleucel|publisher=U.S. [[Food and Drug Administration]] (FDA)}}</ref>
|No
|-
|[[nadofaragene firadenovec]]
|Adstiladrin
|
|[[Ferring Pharmaceuticals]]
|high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS)
|Yes<ref>{{cite press release | title=FDA Approves First Gene Therapy for the Treatment of High-Risk, Non-Muscle-Invasive Bladder Cancer | website=U.S. [[Food and Drug Administration]] (FDA) | date=16 December 2022 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-high-risk-non-muscle-invasive-bladder-cancer | access-date=16 December 2022}}</ref>
|No
|-
|[[onasemnogene abeparvovec]]
|Zolgensma
|In vivo
|[[Novartis Gene Therapies]]
|[[Spinal muscular atrophy]] Type I
|24 May 2019<ref>{{cite web|date=16 March 2021|title=Zolgensma|url=https://www.fda.gov/vaccines-blood-biologics/zolgensma|publisher=U.S. [[Food and Drug Administration]] (FDA)}}</ref>
|26 March 2020<ref>{{cite press release|title=EMA-approved application for Zolgensma|url=https://aetion.com/evidence-hub/fda-decision-alerts/ema-approved-application-for-zolgensma-onasemnogene-abeparvovec-xioi/|access-date=23 July 2021|website=Aetion}}</ref>
|-
|[[talimogene laherparepvec]]
|Imlygic
|In vivo
|[[Amgen]]
|[[melanoma]]
|27 October 2015<ref>{{cite web|date=25 November 2015|title=FDA Approves T-VEC to Treat Metastatic Melanoma - National Cancer Institute|url=https://www.cancer.gov/news-events/cancer-currents-blog/2015/t-vec-melanoma|access-date=23 July 2021|website=National Cancer Institute}}</ref>
|16 December 2015<ref>{{cite web|title=Imlygic|url=https://www.ema.europa.eu/en/medicines/human/EPAR/imlygic|website=[[European Medicines Agency]] (EMA) }}</ref>
|-
|[[tisagenlecleucel]]
|Kymriah
|
|
|B cell lymphoblastic leukemia
|
|22 August 2018
|-
|[[valoctocogene roxaparvovec]]
|Roctavian
|
|[[BioMarin Pharmaceutical|BioMarin International Limited]]
|[[hemophilia A]]
|
|August 2022<ref>{{cite press release | title=First gene therapy to treat severe haemophilia A | website=[[European Medicines Agency]] (EMA) | date=24 June 2022 | url=https://www.ema.europa.eu/en/news/first-gene-therapy-treat-severe-haemophilia | access-date=26 June 2022 | archive-date=26 June 2022 | archive-url=https://web.archive.org/web/20220626014840/https://www.ema.europa.eu/en/news/first-gene-therapy-treat-severe-haemophilia | url-status=live }}</ref><ref name="Roctavian: Pending EC decision">{{cite web | title=Roctavian: Pending EC decision | website=[[European Medicines Agency]] (EMA) | date=23 June 2022 | url=https://www.ema.europa.eu/en/medicines/human/summaries-opinion/roctavian | access-date=26 June 2022 | archive-date=26 June 2022 | archive-url=https://web.archive.org/web/20220626014831/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/roctavian | url-status=live }}</ref><ref name="Roctavian auth">{{cite web | title=Roctavian | website=Union Register of medicinal products | date=25 August 2022 | url=https://ec.europa.eu/health/documents/community-register/html/h1668.htm | access-date=6 September 2022}}</ref>
|-
|[[voretigene neparvovec]]
|Luxturna
|In vivo
|[[Spark Therapeutics]]
|biallelic [[RPE65]] mutation associated [[Leber congenital amaurosis]]
|18 December 2017<ref>{{cite press release|date=24 March 2020|title=FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss|url=https://www.fda.gov/news-events/press-announcements/fda-approves-novel-gene-therapy-treat-patients-rare-form-inherited-vision-loss|access-date=23 July 2021|website=U.S. [[Food and Drug Administration]] (FDA)}}</ref>
|22 November 2018<ref>{{cite web|title=Luxturna|url=https://www.ema.europa.eu/en/medicines/human/EPAR/luxturna|website=[[European Medicines Agency]] (EMA)}}</ref>
|-
|}

==Adverse effects, contraindications and hurdles for use==
Some of the unsolved problems include:
* Short-lived nature – Before gene therapy can become a permanent cure for a condition, the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be stable. Problems with integrating therapeutic DNA into the [[genome]] and the rapidly dividing nature of many cells prevent it from achieving long-term benefits. Patients require multiple treatments.
* Immune response – Any time a foreign object is introduced into human tissues, the immune system is stimulated to attack the invader. Stimulating the immune system in a way that reduces gene therapy effectiveness is possible. The [[immune system]]'s enhanced response to viruses that it has seen before reduces the effectiveness to repeated treatments.
* Problems with viral vectors – Viral vectors carry the risks of toxicity, inflammatory responses, and gene control and targeting issues.
* Multigene disorders – Some commonly occurring disorders, such as [[heart disease]], [[high blood pressure]], [[Alzheimer's disease]], [[arthritis]], and [[diabetes]], are affected by variations in multiple genes, which complicate gene therapy.
* Some therapies may breach the [[Weismann barrier]] (between soma and germ-line) protecting the testes, potentially modifying the germline, falling afoul of regulations in countries that prohibit the latter practice.<ref>{{cite web|title=The implications of Steele's soma-to-germline feedback for human gene therapy|url=http://wasdarwinwrong.com/kortho39a.htm|vauthors=Korthof G}}</ref>
* Insertional [[mutagenesis]] – If the DNA is integrated in a sensitive spot in the genome, for example in a [[tumor suppressor gene]], the therapy could induce a [[tumor]]. This has occurred in clinical trials for [[X-linked severe combined immunodeficiency]] (X-SCID) patients, in which [[hematopoietic]] stem cells were transduced with a corrective transgene using a [[retrovirus]], and this led to the development of [[T cell leukemia]] in 3 of 20 patients.<ref>{{cite journal|vauthors=Woods NB, Bottero V, Schmidt M, von Kalle C, Verma IM|date=April 2006|title=Gene therapy: therapeutic gene causing lymphoma|journal=Nature|volume=440|issue=7088|pages=1123|bibcode=2006Natur.440.1123W|doi=10.1038/4401123a|pmid=16641981|s2cid=4372110|doi-access=free}}</ref><ref>{{cite journal|display-authors=6|vauthors=Thrasher AJ, Gaspar HB, Baum C, Modlich U, Schambach A, Candotti F, Otsu M, Sorrentino B, Scobie L, Cameron E, Blyth K, Neil J, Abina SH, Cavazzana-Calvo M, Fischer A |date=September 2006|title=Gene therapy: X-SCID transgene leukaemogenicity|journal=Nature|volume=443|issue=7109|pages=E5-6; discussion E6-7|bibcode=2006Natur.443E...5T|doi=10.1038/nature05219|pmid=16988659|s2cid=4301764}}</ref> One possible solution is to add a functional tumor suppressor gene to the DNA to be integrated. This may be problematic since the longer the DNA is, the harder it is to integrate into cell genomes.<ref>{{cite journal|vauthors=Bak RO, Porteus MH|date=July 2017|title=CRISPR-Mediated Integration of Large Gene Cassettes Using AAV Donor Vectors|journal=Cell Reports|volume=20|issue=3|pages=750–756|doi=10.1016/j.celrep.2017.06.064|pmc=5568673|pmid=28723575}}</ref> [[CRISPR]] technology allows researchers to make much more precise genome changes at exact locations.<ref name="MIT">{{cite web|last=Rojahn|first=Susan Young|date=11 February 2014|title=Genome Surgery|url=http://www.technologyreview.com/review/524451/genome-surgery/|access-date=17 February 2014|work=MIT Technology Review|name-list-style=vanc}}</ref>
* Cost – [[Alipogene tiparvovec]] or Glybera, for example, at a cost of $1.6 million per patient, was reported in 2013, to be the world's most expensive drug.<ref>{{cite magazine | title=Gene therapy needs a hero to live up to the hype | website=New Scientist | date=30 October 2013 | url=https://www.newscientist.com/article/mg22029412-100-gene-therapy-needs-a-hero-to-live-up-to-the-hype/ | access-date=2 January 2022 | name-list-style=vanc }}</ref><ref>{{cite web|last=Crasto|first=Anthony Melvin|date=7 July 2013|title=Glybera – The Most Expensive Drug in the world & First Approved Gene Therapy in the West|url=http://www.allfordrugs.com/2013/07/16/glybera-the-most-expensive-drug-in-the-world-first-approved-gene-therapy-in-the-west/|access-date=2 November 2013|work=All About Drugs|name-list-style=vanc}}</ref>

===Deaths===
Three patients' deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that of [[Jesse Gelsinger]], who died in 1999, because of immune rejection response.<ref>{{cite web | title=Gene Therapy | website=Oak Ridge National Laboratory | date=20 December 2012 | url=http://www.ornl.gov/sci/techresources/Human_Genome/medicine/genetherapy.shtml | archive-url=https://web.archive.org/web/20121220083825/https://www.ornl.gov/sci/techresources/Human_Genome/medicine/genetherapy.shtml | archive-date=20 December 2012 | url-status=dead | access-date=2 January 2022}}</ref><ref>{{cite journal|display-authors=6|vauthors=Raper SE, Chirmule N, Lee FS, Wivel NA, Bagg A, Gao GP, Wilson JM, Batshaw ML|date=September 2003|title=Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer|journal=Molecular Genetics and Metabolism|volume=80|issue=1–2|pages=148–58|doi=10.1016/j.ymgme.2003.08.016|pmid=14567964}}</ref> One X-SCID patient died of leukemia in 2003.<ref name="Gene Therapy Finds Its Niche" /> In 2007, a [[rheumatoid arthritis]] patient died from an infection; the subsequent investigation concluded that the death was not related to gene therapy.<ref>{{cite journal|display-authors=6|vauthors=Frank KM, Hogarth DK, Miller JL, Mandal S, Mease PJ, Samulski RJ, Weisgerber GA, Hart J|date=July 2009|title=Investigation of the cause of death in a gene-therapy trial|journal=The New England Journal of Medicine|volume=361|issue=2|pages=161–9|doi=10.1056/NEJMoa0801066|pmid=19587341}}</ref>

==Regulations==
Regulations covering genetic modification are part of general guidelines about human-involved biomedical research.{{citation needed|date=January 2022}} There are no international treaties which are legally binding in this area, but there are recommendations for national laws from various bodies.{{citation needed|date=January 2022}}

The [[Declaration of Helsinki|Helsinki Declaration]] (Ethical Principles for Medical Research Involving Human Subjects) was amended by the [[World Medical Association]]'s General Assembly in 2008. This document provides principles physicians and researchers must consider when involving humans as research subjects. The Statement on Gene Therapy Research initiated by the [[Human Genome Organization]] (HUGO) in 2001, provides a legal baseline for all countries. HUGO's document emphasizes human freedom and adherence to human rights, and offers recommendations for somatic gene therapy, including the importance of recognizing public concerns about such research.<ref name="human genome">Human Genome Organization. HUGO Ethics Committee (April 2001). [https://web.archive.org/web/20080907065932/http://www.hugo-international.org/img/gene_2001.pdf Statement on Gene Therapy Research].</ref>

===United States===
No federal legislation lays out protocols or restrictions about human genetic engineering. This subject is governed by overlapping regulations from local and federal agencies, including the [[Department of Health and Human Services]], the FDA and NIH's Recombinant DNA Advisory Committee. Researchers seeking federal funds for an investigational new drug application, (commonly the case for somatic human genetic engineering,) must obey international and federal guidelines for the protection of human subjects.<ref name="regulatory">{{cite web|last1=Isasi|first1=Rosario M.|last2=Nguyen|first2=Thu Minh|last3=Knoppers|first3=Bartha M.|date=October 2006|title=National Regulatory Frameworks Regarding Human Genetic Modification Technologies (Somatic and Germline Modification)|url=http://www.dnapolicy.org/pdf/geneticModification.pdf|url-status=dead|archive-url=https://web.archive.org/web/20140917192159/http://www.dnapolicy.org/pdf/geneticModification.pdf|archive-date=17 September 2014|publisher=Genetics & Public Policy Center|name-list-style=vanc}}</ref>

NIH serves as the main gene therapy regulator for federally funded research. Privately funded research is advised to follow these regulations. NIH provides funding for research that develops or enhances genetic engineering techniques and to evaluate the ethics and quality in current research. The NIH maintains a mandatory registry of human genetic engineering research protocols that includes all federally funded projects.<ref>{{Cite web |title=Home - NIH Genetic Testing Registry (GTR) - NCBI |url=https://www.ncbi.nlm.nih.gov/gtr/ |access-date=2 May 2022 |website=www.ncbi.nlm.nih.gov}}</ref>

An NIH advisory committee published a set of guidelines on gene manipulation.<ref name="national">National Institutes of Health. [http://osp.od.nih.gov/office-biotechnology-activities/biosafety/nih-guidelines NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules]. Revised April 2016.</ref> The guidelines discuss lab safety as well as human test subjects and various experimental types that involve genetic changes. Several sections specifically pertain to human genetic engineering, including Section III-C-1. This section describes required review processes and other aspects when seeking approval to begin clinical research involving genetic transfer into a human patient.<ref name="us">{{cite web | title=Read the Belmont Report | website=HHS.gov | date=15 January 2018 | url=https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html | access-date=2 January 2022}}</ref> The protocol for a gene therapy clinical trial must be approved by the NIH's Recombinant DNA Advisory Committee prior to any clinical trial beginning; this is different from any other kind of clinical trial.<ref name="national" />

As with other kinds of drugs, the FDA regulates the quality and safety of gene therapy products and supervises how these products are used clinically. Therapeutic alteration of the human genome falls under the same regulatory requirements as any other medical treatment. Research involving human subjects, such as [[clinical trials]], must be reviewed and approved by the FDA and an [[Institutional Review Board]].<ref name="fda2">{{cite journal|author=U.S. Food and Drug Administration|date=14 October 1993|title=Application of Current Statutory Authorities to Human Somatic Cell Therapy Products and Gene Therapy Products|url=https://www.fda.gov/downloads/BiologicsBloodVaccines/SafetyAvailability/UCM148113.pdf |archive-url=https://web.archive.org/web/20090621183818/http://www.fda.gov/downloads/BiologicsBloodVaccines/SafetyAvailability/UCM148113.pdf |archive-date=21 June 2009 |url-status=live|journal=Federal Register|volume=58|issue=197}}</ref><ref name="health">{{cite web | title=Guidance for Industry: Guidance for Human Somatic Cell Therapy and Gene Therapy | website=fda.gov | date=9 July 2009 | url=https://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/cellularandgenetherapy/ucm072987.htm | archive-url=https://web.archive.org/web/20090709195400/https://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/cellularandgenetherapy/ucm072987.htm | archive-date=9 July 2009 | url-status=dead | access-date=2 January 2022}}</ref>

==History==
{{Summarize section|date=November 2018}}

===1970s and earlier===
In 1972, Friedmann and Roblin authored a paper in ''[[Science (journal)|Science]]'' titled "Gene therapy for human genetic disease?".<ref name="Friedman 1972">{{cite journal | vauthors = Friedmann T, Roblin R | title = Gene therapy for human genetic disease? | journal = Science | volume = 175 | issue = 4025 | pages = 949–955 | date = March 1972 | pmid = 5061866 | doi = 10.1126/science.175.4025.949 | bibcode = 1972Sci...175..949F | s2cid = 19952096 }}</ref> Rogers (1970) was cited for proposing that ''exogenous good DNA'' be used to replace the defective DNA in those with genetic defects.<ref>Rogers S, New Scientist 1970, p.&nbsp;194</ref>

===1980s===
In 1984, a retrovirus vector system was designed that could efficiently insert foreign genes into mammalian chromosomes.<ref>{{cite journal | vauthors = Cepko CL, Roberts BE, Mulligan RC | title = Construction and applications of a highly transmissible murine retrovirus shuttle vector. This Vector is used for entering a cell in the humans cell body. | journal = Cell | volume = 37 | issue = 3 | pages = 1053–1062 | date = July 1984 | pmid = 6331674 | doi = 10.1016/0092-8674(84)90440-9 | s2cid = 34544709 }}</ref>

===1990s===
The first approved gene therapy clinical research in the US took place on 14 September 1990, at the [[National Institutes of Health]] (NIH), under the direction of [[William French Anderson]].<ref>{{cite web|url=http://www.lifesciencesfoundation.org/printer_events-The_first_gene_therapy.html |title=The first gene therapy |publisher=Life Sciences Foundation |date=21 June 2011 |access-date=7 January 2014 |url-status=dead |archive-url=https://web.archive.org/web/20121128203817/http://www.lifesciencesfoundation.org/printer_events-The_first_gene_therapy.html |archive-date=28 November 2012 }}</ref> Four-year-old Ashanti DeSilva received treatment for a genetic defect that left her with [[adenosine deaminase deficiency]] (ADA-SCID), a severe immune system deficiency. The defective gene of the patient's blood cells was replaced by the functional variant. Ashanti's immune system was partially restored by the therapy. Production of the missing enzyme was temporarily stimulated, but the new cells with functional genes were not generated. She led a normal life only with the regular injections performed every two months. The effects were successful, but temporary.<ref>{{cite journal | vauthors = Blaese RM, Culver KW, Miller AD, Carter CS, Fleisher T, Clerici M, Shearer G, Chang L, Chiang Y, Tolstoshev P, Greenblatt JJ, Rosenberg SA, Klein H, Berger M, Mullen CA, Ramsey WJ, Muul L, Morgan RA, Anderson WF | display-authors = 6 | title = T lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years | journal = Science | volume = 270 | issue = 5235 | pages = 475–480 | date = October 1995 | pmid = 7570001 | doi = 10.1126/science.270.5235.475 | bibcode = 1995Sci...270..475B | s2cid = 46339645 | url = https://zenodo.org/record/1231045 }}</ref>

Cancer gene therapy was introduced in 1992/93 (Trojan et al. 1993).<ref>{{cite journal | vauthors = Trojan J, Johnson TR, Rudin SD, Ilan J, Tykocinski ML, Ilan J | title = Treatment and prevention of rat glioblastoma by immunogenic C6 cells expressing antisense insulin-like growth factor I RNA | journal = Science | volume = 259 | issue = 5091 | pages = 94–97 | date = January 1993 | pmid = 8418502 | doi = 10.1126/science.8418502 | bibcode = 1993Sci...259...94T }}</ref> The treatment of [[glioblastoma]] multiforme, the malignant brain tumor whose outcome is always fatal, was done using a vector expressing antisense IGF-I RNA (clinical trial approved by NIH protocol no.1602 24 November 1993,<ref name="pmid22400112">{{cite journal | vauthors = Trojan J, Pan YX, Wei MX, Ly A, Shevelev A, Bierwagen M, Ardourel MY, Trojan LA, Alvarez A, Andres C, Noguera MC, Briceno I, Aristizabal BH, Kasprzak H, Duc HT, Anthony DD | display-authors = 6 | title = Methodology for Anti-Gene Anti-IGF-I Therapy of Malignant Tumours | journal = Chemotherapy Research and Practice | volume = 2012 | pages = 1–12 | year = 2012 | pmid = 22400112 | pmc = 3287029 | doi = 10.1155/2012/721873 | doi-access = free }}</ref> and by the FDA in 1994). This therapy also represents the beginning of cancer immunogene therapy, a treatment which proves to be effective due to the anti-tumor mechanism of IGF-I antisense, which is related to strong immune and apoptotic phenomena.

In 1992, [[Claudio Bordignon]], working at the [[Vita-Salute San Raffaele University]], performed the first gene therapy procedure using [[hematopoietic stem cell]]s as vectors to deliver genes intended to correct [[hereditary diseases]].<ref>{{cite journal | vauthors = Abbott A | title = Gene therapy. Italians first to use stem cells | journal = Nature | volume = 356 | issue = 6369 | pages = 465 | date = April 1992 | pmid = 1560817 | doi = 10.1038/356465a0 | bibcode = 1992Natur.356..465A | s2cid = 4319842 }}</ref> In 2002, this work led to the publication of the first successful gene therapy treatment for ADA-SCID. The success of a multi-center trial for treating children with SCID ([[severe combined immune deficiency]] or "bubble boy" disease) from 2000 and 2002, was questioned when two of the ten children treated at the trial's Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the US, the United Kingdom, France, Italy, and Germany.<ref>{{cite journal | vauthors = Cavazzana-Calvo M, Thrasher A, Mavilio F | title = The future of gene therapy | journal = Nature | volume = 427 | issue = 6977 | pages = 779–781 | date = February 2004 | pmid = 14985734 | doi = 10.1038/427779a | bibcode = 2004Natur.427..779C | s2cid = 4421364 }}</ref>

In 1993, Andrew Gobea was born with SCID following prenatal [[genetic screening]]. Blood was removed from his mother's [[placenta]] and [[umbilical cord]] immediately after birth, to acquire stem cells. The [[allele]] that codes for [[adenosine deaminase]] (ADA) was obtained and inserted into a retrovirus. Retroviruses and stem cells were mixed, after which the viruses inserted the gene into the stem cell chromosomes. Stem cells containing the working ADA gene were injected into Andrew's blood. Injections of the ADA enzyme were also given weekly. For four years [[T cell]]s (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed.<ref>{{cite news|url=https://www.nytimes.com/1993/05/18/science/treatment-for-bubble-boy-disease.html|title=Treatment for 'Bubble Boy Disease'|last1=S|date=18 May 1993|work=The New York Times|access-date=9 February 2018|last2=Blakeslee|first2=Ra|issn=0362-4331 | name-list-style = vanc }}</ref>

[[Jesse Gelsinger]]'s death in 1999 impeded gene therapy research in the US.<ref>{{cite news|url=https://www.washingtonpost.com/wp-dyn/content/article/2010/10/11/AR2010101102946.html |title=First patient treated in stem cell study |newspaper=The Washington Post |date= 11 October 2010 | last = Stein | first = Rob | name-list-style = vanc | access-date = 10 November 2010 }}</ref><ref>{{cite web|url=http://www.medpagetoday.com/Genetics/GeneralGenetics/6275 |title=Death Prompts FDA to Suspend Arthritis Gene Therapy Trial |publisher=Medpage Today |date= 27 July 2007 |access-date=10 November 2010}}</ref> As a result, the FDA suspended several clinical trials pending the reevaluation of ethical and procedural practices.<ref>{{cite news|url=https://www.nytimes.com/2000/01/22/us/gene-therapy-ordered-halted-at-university.html | last = Stolberg | first = Sheryl Gay | name-list-style = vanc | title=Gene Therapy Ordered Halted At University |work=The New York Times |date=22 January 2000 |access-date=10 November 2010 }}</ref>

===2000s===
The modified gene therapy strategy of antisense IGF-I RNA (NIH n˚ 1602)<ref name="pmid22400112" /> using antisense / triple helix anti-IGF-I approach was registered in 2002, by Wiley gene therapy clinical trial - n˚ 635 and 636. The approach has shown promising results in the treatment of six different malignant tumors: [[glioblastoma]], cancers of liver, colon, prostate, uterus, and ovary (Collaborative NATO Science Programme on Gene Therapy USA, France, Poland n˚ LST 980517 conducted by J. Trojan) (Trojan et al., 2012). This anti-gene antisense/triple helix therapy has proven to be efficient, due to the mechanism stopping simultaneously IGF-I expression on translation and transcription levels, strengthening anti-tumor immune and apoptotic phenomena.

====2002====
[[Sickle cell disease]] can be treated in mice.<ref>{{cite web|url=http://www.the-scientist.com/article/display/12938/ |title=Murine Gene Therapy Corrects Symptoms of Sickle Cell Disease|work=The Scientist – Magazine of the Life Sciences| last = Wilson | first = Jennifer Fisher | name-list-style = vanc |date=18 March 2002 |access-date=17 August 2010 }}</ref> The mice – which have essentially the same defect that causes human cases – used a viral vector to induce production of [[fetal hemoglobin]] (HbF), which normally ceases to be produced shortly after birth. In humans, the use of [[hydroxyurea]] to stimulate the production of HbF temporarily alleviates sickle cell symptoms. The researchers demonstrated this treatment to be a more permanent means to increase therapeutic HbF production.<ref name="St Jude">{{cite web|last=St. Jude Children's Research Hospital|title=Gene Therapy Corrects Sickle Cell Disease In Laboratory Study|url=https://www.sciencedaily.com/releases/2008/12/081203184643.htm|website=ScienceDaily|access-date=29 December 2012|date=4 December 2008}}</ref>

A new gene therapy approach repaired errors in [[messenger RNA]] derived from defective genes. This technique has the potential to treat [[thalassaemia]], [[cystic fibrosis]] and some cancers.<ref>{{cite web|url=https://www.newscientist.com/article/dn2915-subtle-gene-therapy-tackles-blood-disorder.html |title=Subtle gene therapy tackles blood disorder |date= 11 October 2002| last = Penman | first = Danny | name-list-style = vanc |work=New Scientist |access-date=17 August 2010}}</ref>

Researchers created [[liposomes]] 25 nanometers across that can carry therapeutic DNA through pores in the [[nuclear membrane]].<ref>{{cite web|url=https://www.newscientist.com/article/dn2257-dna-nanoballs-boost-gene-therapy.html |title=DNA nanoballs boost gene therapy |work=New Scientist |date=12 May 2002 |access-date=17 August 2010}}</ref>

====2003====
In 2003, a research team inserted genes into the brain for the first time. They used [[liposomes]] coated in a [[polymer]] called [[polyethylene glycol]], which unlike viral vectors, are small enough to cross the [[blood–brain barrier]].<ref>{{cite web|url=https://www.newscientist.com/article/dn3520-undercover-genes-slip-into-the-brain.html | last = Ananthaswamy | first = Anil | name-list-style = vanc |title=Undercover genes slip into the brain |work=New Scientist |date=20 March 2003 |access-date=17 August 2010}}</ref>

Short pieces of [[double-stranded RNA]] (short, interfering RNAs or [[siRNA]]s) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced.<ref>{{cite web|url=https://www.newscientist.com/article/dn3493-gene-therapy-may-switch-off-huntingtons.html |title=Gene therapy may switch off Huntington's |work=New Scientist |date=13 March 2003 |access-date=17 August 2010| last = Holmes | first = Bob | name-list-style = vanc }}</ref>

[[Gendicine]] is a cancer gene therapy that delivers the [[tumor suppressor]] gene [[p53]] using an engineered [[adenovirus]]. In 2003, it was approved in China for the treatment of [[Head and neck cancer|head and neck squamous cell carcinoma]].<ref name="Gend" />

====2006====
In March, researchers announced the successful use of gene therapy to treat two adult patients for X-linked [[chronic granulomatous disease]], a disease which affects [[myeloid]] cells and damages the [[immune system]]. The study is the first to show that gene therapy can treat the myeloid system.<ref>{{cite journal | vauthors = Ott MG, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U, Glimm H, Kühlcke K, Schilz A, Kunkel H, Naundorf S, Brinkmann A, Deichmann A, Fischer M, Ball C, Pilz I, Dunbar C, Du Y, Jenkins NA, Copeland NG, Lüthi U, Hassan M, Thrasher AJ, Hoelzer D, von Kalle C, Seger R, Grez M | display-authors = 6 | title = Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1 | journal = Nature Medicine | volume = 12 | issue = 4 | pages = 401–409 | date = April 2006 | pmid = 16582916 | doi = 10.1038/nm1393 | s2cid = 7601162 | url = http://www.medscape.com/viewarticle/531129 }}</ref>

In May, a team reported a way to prevent the immune system from rejecting a newly delivered gene.<ref>{{cite journal | vauthors = Brown BD, Venneri MA, Zingale A, Sergi Sergi L, Naldini L | title = Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer | journal = Nature Medicine | volume = 12 | issue = 5 | pages = 585–591 | date = May 2006 | pmid = 16633348 | doi = 10.1038/nm1398 | s2cid = 11114427 }}</ref> Similar to [[organ transplant]]ation, gene therapy has been plagued by this problem. The immune system normally recognizes the new gene as foreign and rejects the cells carrying it. The research utilized a newly uncovered network of genes regulated by molecules known as [[microRNA]]s. This natural function selectively obscured their therapeutic gene in immune system cells and protected it from discovery. Mice infected with the gene containing an immune-cell microRNA target sequence did not reject the gene.

In August, scientists successfully treated metastatic [[melanoma]] in two patients using [[Cytotoxic T cell|killer T cells]] genetically retargeted to attack the cancer cells.<ref>{{cite journal | vauthors = Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, de Vries CR, Rogers-Freezer LJ, Mavroukakis SA, Rosenberg SA | display-authors = 6 | title = Cancer regression in patients after transfer of genetically engineered lymphocytes | journal = Science | volume = 314 | issue = 5796 | pages = 126–129 | date = October 2006 | pmid = 16946036 | pmc = 2267026 | doi = 10.1126/science.1129003 | bibcode = 2006Sci...314..126M }}</ref>

In November, researchers reported on the use of VRX496, a gene-based [[immunotherapy]] for the treatment of [[HIV]] that uses a [[lentivirus|lentiviral]] [[viral vector|vector]] to deliver an [[Sense (molecular biology)|antisense]] gene against the [[HIV envelope]]. In a [[phase I clinical trial]], five subjects with chronic HIV infection who had failed to respond to at least two [[antiretroviral]] regimens were treated. A single intravenous infusion of [[autologous]] [[CD4]] T cells genetically modified with VRX496 was well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. All five patients had stable or increased immune response to HIV [[antigen]]s and other [[pathogen]]s. This was the first evaluation of a lentiviral vector administered in a US human clinical trial.<ref>{{cite journal | vauthors = Levine BL, Humeau LM, Boyer J, MacGregor RR, Rebello T, Lu X, Binder GK, Slepushkin V, Lemiale F, Mascola JR, Bushman FD, Dropulic B, June CH | display-authors = 6 | title = Gene transfer in humans using a conditionally replicating lentiviral vector | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 46 | pages = 17372–17377 | date = November 2006 | pmid = 17090675 | pmc = 1635018 | doi = 10.1073/pnas.0608138103 | bibcode = 2006PNAS..10317372L | doi-access = free }}</ref><ref>{{cite web|url=http://www.eurekalert.org/pub_releases/2009-02/uops-pmp021009.php|date=10 February 2009|title=Penn Medicine presents HIV gene therapy trial data at CROI 2009|access-date=19 November 2009|website=EurekAlert!}}</ref>

====2007====
In May, researchers announced the first gene therapy trial for inherited [[retinal disease]]. The first operation was carried out on a 23-year-old British male, Robert Johnson, in early 2007.<ref>{{cite news| url=http://news.bbc.co.uk/1/hi/health/6609205.stm | work=BBC News | title=Gene therapy first for poor sight | date=1 May 2007 | access-date=3 May 2010}}</ref>

====2008====
{{Main|Gene therapy of the human retina}}

[[Leber's congenital amaurosis]] is an inherited blinding disease caused by mutations in the [[RPE65]] gene. The results of a small clinical trial in children were published in April.<ref name="Maguire 2008"/> Delivery of recombinant [[adeno-associated virus]] (AAV) carrying RPE65 yielded positive results. In May, two more groups reported positive results in independent clinical trials using gene therapy to treat the condition. In all three clinical trials, patients recovered functional vision without apparent side-effects.<ref name="Maguire 2008">{{cite journal | vauthors = Maguire AM, Simonelli F, Pierce EA, Pugh EN, Mingozzi F, Bennicelli J, Banfi S, Marshall KA, Testa F, Surace EM, Rossi S, Lyubarsky A, Arruda VR, Konkle B, Stone E, Sun J, Jacobs J, Dell'Osso L, Hertle R, Ma JX, Redmond TM, Zhu X, Hauck B, Zelenaia O, Shindler KS, Maguire MG, Wright JF, Volpe NJ, McDonnell JW, Auricchio A, High KA, Bennett J | display-authors = 6 | title = Safety and efficacy of gene transfer for Leber's congenital amaurosis | journal = The New England Journal of Medicine | volume = 358 | issue = 21 | pages = 2240–2248 | date = May 2008 | pmid = 18441370 | pmc = 2829748 | doi = 10.1056/NEJMoa0802315 }}</ref><ref name="Simonelli 2010">{{cite journal | vauthors = Simonelli F, Maguire AM, Testa F, Pierce EA, Mingozzi F, Bennicelli JL, Rossi S, Marshall K, Banfi S, Surace EM, Sun J, Redmond TM, Zhu X, Shindler KS, Ying GS, Ziviello C, Acerra C, Wright JF, McDonnell JW, High KA, Bennett J, Auricchio A | display-authors = 6 | title = Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration | journal = Molecular Therapy | volume = 18 | issue = 3 | pages = 643–650 | date = March 2010 | pmid = 19953081 | pmc = 2839440 | doi = 10.1038/mt.2009.277 }}</ref><ref name="Cideciyan 2009">{{cite journal | vauthors = Cideciyan AV, Hauswirth WW, Aleman TS, Kaushal S, Schwartz SB, Boye SL, Windsor EA, Conlon TJ, Sumaroka A, Roman AJ, Byrne BJ, Jacobson SG | title = Vision 1 year after gene therapy for Leber's congenital amaurosis | journal = The New England Journal of Medicine | volume = 361 | issue = 7 | pages = 725–727 | date = August 2009 | pmid = 19675341 | pmc = 2847775 | doi = 10.1056/NEJMc0903652 }}</ref><ref name="Bainbridge 2008">{{cite journal | vauthors = Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, Stockman A, Tyler N, Petersen-Jones S, Bhattacharya SS, Thrasher AJ, Fitzke FW, Carter BJ, Rubin GS, Moore AT, Ali RR | display-authors = 6 | title = Effect of gene therapy on visual function in Leber's congenital amaurosis | journal = The New England Journal of Medicine | volume = 358 | issue = 21 | pages = 2231–2239 | date = May 2008 | pmid = 18441371 | doi = 10.1056/NEJMoa0802268 | hdl = 10261/271174 }}</ref>

====2009====
In September researchers were able to give [[trichromatic vision]] to [[squirrel monkeys]].<ref>{{cite journal | last1 = Dolgin | first1 = E. | name-list-style = vanc | title = Colour blindness corrected by gene therapy | journal = Nature | year = 2009 | doi = 10.1038/news.2009.921 }}</ref> In November 2009, researchers halted a fatal [[genetic disorder]] called [[adrenoleukodystrophy]] in two children using a [[lentivirus]] vector to deliver a functioning version of [[ABCD1]], the gene that is mutated in the disorder.<ref name="pmid19892975">{{cite journal | vauthors = Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, Vidaud M, Abel U, Dal-Cortivo L, Caccavelli L, Mahlaoui N, Kiermer V, Mittelstaedt D, Bellesme C, Lahlou N, Lefrère F, Blanche S, Audit M, Payen E, Leboulch P, l'Homme B, Bougnères P, Von Kalle C, Fischer A, Cavazzana-Calvo M, Aubourg P | s2cid = 27783 | display-authors = 6 | title = Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy | journal = Science | volume = 326 | issue = 5954 | pages = 818–823 | date = November 2009 | pmid = 19892975 | doi = 10.1126/science.1171242 | bibcode = 2009Sci...326..818C }}</ref>

===2010s===
====2010====
An April paper reported that gene therapy addressed [[achromatopsia]] (color blindness) in dogs by targeting [[Cone (vision)|cone]] photoreceptors. Cone function and day vision were restored for at least 33 months in two young specimens. The therapy was less efficient for older dogs.<ref name="Komáromy">{{cite journal | vauthors = Komáromy AM, Alexander JJ, Rowlan JS, Garcia MM, Chiodo VA, Kaya A, Tanaka JC, Acland GM, Hauswirth WW, Aguirre GD | display-authors = 6 | title = Gene therapy rescues cone function in congenital achromatopsia | journal = Human Molecular Genetics | volume = 19 | issue = 13 | pages = 2581–2593 | date = July 2010 | pmid = 20378608 | pmc = 2883338 | doi = 10.1093/hmg/ddq136 }}</ref>

In September it was announced that an 18-year-old male patient in France with [[beta thalassemia]] major had been successfully treated.<ref>{{cite journal | vauthors = Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F, Down J, Denaro M, Brady T, Westerman K, Cavallesco R, Gillet-Legrand B, Caccavelli L, Sgarra R, Maouche-Chrétien L, Bernaudin F, Girot R, Dorazio R, Mulder GJ, Polack A, Bank A, Soulier J, Larghero J, Kabbara N, Dalle B, Gourmel B, Socie G, Chrétien S, Cartier N, Aubourg P, Fischer A, Cornetta K, Galacteros F, Beuzard Y, Gluckman E, Bushman F, Hacein-Bey-Abina S, Leboulch P | display-authors = 6 | title = Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia | journal = Nature | volume = 467 | issue = 7313 | pages = 318–322 | date = September 2010 | pmid = 20844535 | pmc = 3355472 | doi = 10.1038/nature09328 | bibcode = 2010Natur.467..318C }}</ref> Beta thalassemia major is an inherited [[blood disease]] in which [[HBB|beta haemoglobin]] is missing and patients are dependent on regular lifelong [[blood transfusions]].<ref>{{cite journal | vauthors = Galanello R, Origa R | title = Beta-thalassemia | journal = Orphanet Journal of Rare Diseases | volume = 5 | pages = 11 | date = May 2010 | pmid = 20492708 | pmc = 2893117 | doi = 10.1186/1750-1172-5-11 }}</ref> The technique used a lentiviral vector to transduce the human β-globin gene into purified blood and [[Bone marrow|marrow]] cells obtained from the patient in June 2007.<ref name="medscape1">Beals, Jacquelyn K. (16 September 2010). [http://www.medscape.com/viewarticle/728656 Gene Therapy Frees Beta-Thalassemia Patient From Transfusions for 2+ Years]. Medscape.com (16 September 2010). Retrieved 15 December 2012.</ref> The patient's haemoglobin levels were stable at 9 to 10 g/dL. About a third of the hemoglobin contained the form introduced by the viral vector and blood transfusions were not needed.<ref name="medscape1"/><ref name="Leboulch">{{cite journal | vauthors = Leboulch P | date = 20 March 2013 | url = http://www.pagepressjournals.org/index.php/thal/article/view/thal.2013.s1.e43 | title = Five year outcome of lentiviral gene therapy for human beta-thalassemia, lessons and prospects | journal = Thalassemia Reports | volume = 3 | issue = 1s|page=108 | doi = 10.4081/thal.2013.s1.e43 | doi-access = free }}</ref> Further clinical trials were planned.<ref name = "NCT01639690">{{ClinicalTrialsGov|NCT01639690|β-Thalassemia Major With Autologous CD34+ Hematopoietic Progenitor Cells Transduced With TNS9.3.55 a Lentiviral Vector Encoding the Normal Human β-Globin Gene}}</ref> [[Bone marrow transplant]]s are the only cure for thalassemia, but 75% of patients do not find a matching donor.<ref name="Leboulch" />

Cancer immunogene therapy using modified antigene, antisense/triple helix approach was introduced in South America in 2010/11 in La Sabana University, Bogota (Ethical Committee 14 December 2010, no P-004-10). Considering the ethical aspect of gene diagnostic and gene therapy targeting IGF-I, the IGF-I expressing tumors i.e. lung and epidermis cancers were treated (Trojan et al. 2016).<ref>{{cite journal | vauthors = Trojan A, Aristizabal BH, Jay LM, Castillo T, Penagos PJ, Briceño I, Trojan J | year = 2016| title = IGF-I biomarker testing in an ethical context | url =http://www.advmodoncolres.sg/index.php/amor/article/view/66 | journal = Adv Modern Oncol Res | volume = 2| issue = 4 | pages = 188–200 | doi = 10.18282/amor.v2.i4.58 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Castillo T, Trojan A, Noguera MC, Jay LM, Crane C, Alvarez A, Kasprzak H, Melo G, Penagos PJ, Shevelev A, Aristizabal BH, Briceño I, Ayala A, Duc HT, Trojan J | display-authors=6 | year = 2016 | title = Epistemológica experiencia en la elaboración de tecnología biomolecular para estrategia de la inmunoterapia génica | trans-title = Epistemological experience in developing of molecular biology technology for immunogene therapy strategy | journal = Rev Cien | language = es | volume = 2 | issue = 25 | pages = 228–240 | doi = 10.14483//udistrital.jour.RC.2016.25.a6 | doi-access = free }}</ref>

====2011====
In 2007 and 2008, a man ([[Timothy Ray Brown]]) was cured of HIV by repeated [[hematopoietic stem cell transplantation]] (see also [[allogeneic stem cell transplantation]], [[allogeneic bone marrow transplantation]], [[allotransplantation]]) with double-delta-32 mutation which disables the [[CCR5]] receptor. This cure was accepted by the medical community in 2011.<ref>{{cite magazine | last=Rosenberg | first=Tina | title=The Man Who Was Cured of HIV and What It Means for a Cure for AIDS | website=[[New York (magazine)|New York]] | date=27 May 2011 | url=https://nymag.com/health/features/aids-cure-2011-6/ | access-date=2 January 2022 | name-list-style = vanc}}</ref> It required complete [[Ablation therapy|ablation]] of existing [[bone marrow]], which is very debilitating.<ref>{{Cite web |title=Letters from the Director: Remembering Timothy Ray Brown: A Champion for HIV Cure Research {{!}} NIH Office of AIDS Research |url=https://www.oar.nih.gov/about/directors-corner/remembering-timothy-ray-brown |access-date=26 June 2022 |website=www.oar.nih.gov}}</ref>

In August two of three subjects of a pilot study were confirmed to have been cured from [[chronic lymphocytic leukemia]] (CLL). The therapy used genetically modified [[T cells]] to attack cells that expressed the [[CD19]] protein to fight the disease.<ref name = "Porter">{{cite journal | last1 = Ledford | first1 = H. | name-list-style = vanc | title = Cell therapy fights leukaemia | journal = Nature | year = 2011 | doi = 10.1038/news.2011.472 }}</ref> In 2013, the researchers announced that 26 of 59 patients had achieved complete remission and the original patient had remained tumor-free.<ref>{{cite web|url=http://singularityhub.com/2014/01/06/gene-therapy-delivers-dramatic-success-in-treating-leukemia-will-it-work-for-other-cancers-too/ |title=Gene Therapy Turns Several Leukemia Patients Cancer Free. Will It Work for Other Cancers, Too? |publisher=Singularity Hub |access-date=7 January 2014|date=6 January 2014 }}</ref>

[[Human HGF plasmid DNA therapy]] of [[cardiomyocytes]] is being examined as a potential treatment for [[coronary artery disease]] as well as treatment for the damage that occurs to the heart after [[myocardial infarction]].<ref name="YangZhang2008">{{cite journal | vauthors = Yang ZJ, Zhang YR, Chen B, Zhang SL, Jia EZ, Wang LS, Zhu TB, Li CJ, Wang H, Huang J, Cao KJ, Ma WZ, Wu B, Wang LS, Wu CT | display-authors = 6 | title = Phase I clinical trial on intracoronary administration of Ad-hHGF treating severe coronary artery disease | journal = Molecular Biology Reports | volume = 36 | issue = 6 | pages = 1323–1329 | date = July 2009 | pmid = 18649012 | doi = 10.1007/s11033-008-9315-3 | s2cid = 23419866 }}</ref><ref name="HahnPyun2011">{{cite journal | vauthors = Hahn W, Pyun WB, Kim DS, Yoo WS, Lee SD, Won JH, Shin GJ, Kim JM, Kim S | display-authors = 6 | title = Enhanced cardioprotective effects by coexpression of two isoforms of hepatocyte growth factor from naked plasmid DNA in a rat ischemic heart disease model | journal = The Journal of Gene Medicine | volume = 13 | issue = 10 | pages = 549–555 | date = October 2011 | pmid = 21898720 | doi = 10.1002/jgm.1603 | s2cid = 26812780 }}</ref>

In 2011, [[Neovasculgen]] was registered in Russia as the first-in-class gene-therapy drug for treatment of [[peripheral artery disease]], including [[critical limb ischemia]]; it delivers the gene encoding for [[VEGF]].<ref name="Neuvasculgen" /> Neovasculogen is a [[plasmid]] encoding the [[Cytomegalovirus#Genetic engineering|CMV promoter]] and the 165 amino acid form of [[VEGF]].<ref>Eurolab. [http://www.eurolab.ua/medicine/drugs/5411/ Neovasculogen listing in Eurolab] Page accessed 4 August 2015</ref><ref>{{cite journal | vauthors = Deev RV, Bozo IY, Mzhavanadze ND, Voronov DA, Gavrilenko AV, Chervyakov YV, Staroverov IN, Kalinin RE, Shvalb PG, Isaev AA | display-authors = 6 | title = pCMV-vegf165 Intramuscular Gene Transfer is an Effective Method of Treatment for Patients With Chronic Lower Limb Ischemia | journal = Journal of Cardiovascular Pharmacology and Therapeutics | volume = 20 | issue = 5 | pages = 473–482 | date = September 2015 | pmid = 25770117 | doi = 10.1177/1074248415574336 | s2cid = 13443907 }}</ref>

====2012====
The FDA approved Phase I clinical trials on [[thalassemia]] major patients in the US for 10 participants in July.<ref>{{cite web | url = http://www.mskcc.org/blog/launch-stem-cell-therapy-trial-offers-hope-patients-inherited-blood-disorder | title = On Cancer: Launch of Stem Cell Therapy Trial Offers Hope for Patients with Inherited Blood Disorder | publisher = Memorial Sloan-Kettering Cancer Center | date = 16 July 2012 | access-date = 15 December 2012}}</ref> The study was expected to continue until 2015.<ref name = "NCT01639690" />

In July 2012, the [[European Medicines Agency]] recommended approval of a gene therapy treatment for the first time in either Europe or the United States. The treatment used [[Alipogene tiparvovec]] (Glybera) to compensate for [[lipoprotein lipase deficiency]], which can cause severe [[pancreatitis]].<ref>{{cite web | title=European Agency Recommends Approval of a Gene Therapy | last=Pollack | first=Andrew | website=The New York Times | date=20 July 2012 | url=https://www.nytimes.com/2012/07/21/health/european-agency-recommends-approval-of-a-gene-therapy.html | access-date=2 January 2022 | name-list-style = vanc}}</ref> The recommendation was endorsed by the [[European Commission]] in November 2012,<ref name="Richards2012">{{cite web|last=Richards|first=Sabrina| name-list-style = vanc |title=Gene Therapy Arrives in Europe|url=http://www.the-scientist.com/?articles.view/articleNo/33166/title/Gene-Therapy-Arrives-in-Europe/|work=The Scientist|date=6 November 2012}}</ref><ref name="Gallagher">Gallagher, James. (2 November 2012) [https://www.bbc.co.uk/news/health-20179561 Gene therapy: Glybera approved by European Commission]. BBC News. Retrieved 15 December 2012.</ref><ref>{{cite press release | title=First Gene Therapy Approved by European Commission | website=UniQure | date=2 November 2012 | url=https://www.uniqure.com/news/167/182/uniQure-s-Glybera-First-Gene-Therapy-Approved-by-European-Commission.html | archive-url=https://web.archive.org/web/20121105033602/https://www.uniqure.com/news/167/182/uniQure-s-Glybera-First-Gene-Therapy-Approved-by-European-Commission.html | archive-date=5 November 2012 | url-status=dead | access-date=2 January 2022}}</ref><ref>{{cite web | title = Chiesi and uniQure delay Glybera launch to add data | work = Biotechnology | publisher = [[The Pharma Letter]] | date = 4 August 2014 | url = http://www.thepharmaletter.com/article/chiesi-and-uniqure-delay-glybera-launch-to-add-data | access-date = 28 August 2014 }}</ref> and commercial rollout began in late 2014.<ref name="reuters">{{cite news|url = https://www.reuters.com/article/us-health-genetherapy-price-idUSKCN0JA1TP20141126|title = First gene therapy drug sets million-euro price record|last1 = Burger|first1 = Ludwig| name-list-style = vanc |date = 26 November 2014|work = Reuters|access-date = 30 March 2015|last2 = Hirschler |first2 = Ben}}</ref> Alipogene tiparvovec was expected to cost around $1.6 million per treatment in 2012,<ref>{{cite news | work=[[The Wall Street Journal]] | first= Jeanne | last = Whalen | name-list-style = vanc | url = https://www.wsj.com/articles/SB10001424052970203707604578095091940871524 | date=2 November 2012 | title=Gene-Therapy Approval Marks Major Milestone | url-access=subscription }}</ref> revised to $1 million in 2015,<ref>{{cite journal |journal=TradeSecrets | first = Chris | last = Morrison | name-list-style = vanc | date= 3 March 2015 | title=$1-million price tag set for Glybera gene therapy| volume = 33 | issue = 3 | pages = 217–218 | doi = 10.1038/nbt0315-217 | pmid = 25748892 | s2cid = 205266596 }}</ref> making it the most expensive medicine in the world at the time.<ref>{{Cite web|url=http://www.bionews.org.uk/page_204696.asp |archive-url=https://web.archive.org/web/20140104002400/http://www.bionews.org.uk/page_204696.asp |archive-date=4 January 2014 |title=Gene therapy approved in Europe for first time}}</ref> {{as of|2016}}, only the patients treated in clinical trials and a patient who paid the full price for treatment have received the drug.<ref name="MIT-TR2016">{{cite news|last1=Regalado|first1=Antonio| name-list-style = vanc |title=The World's Most Expensive Medicine Is a Bust|url=https://www.technologyreview.com/s/601165/the-worlds-most-expensive-medicine-is-a-bust/amp/|work=MIT Technology Review|date=4 May 2016}}</ref>

In December 2012, it was reported that 10 of 13 patients with [[multiple myeloma]] were in remission "or very close to it" three months after being injected with a treatment involving genetically engineered [[T cells]] to target proteins [[NY-ESO-1]] and [[LAGE-1]], which exist only on cancerous myeloma cells.<ref name="Adaptimmune" />

====2013====
In March researchers reported that three of five adult subjects who had [[acute lymphocytic leukemia]] (ALL) had been in remission for five months to two years after being treated with genetically modified [[T cells]] which attacked cells with [[CD19]] genes on their surface, i.e. all [[B cell]]s, cancerous or not. The researchers believed that the patients' immune systems would make normal T cells and B cells after a couple of months. They were also given bone marrow. One patient relapsed and died and one died of a blood clot unrelated to the disease.<ref name="SloanKettering">{{cite web |vauthors=Coghlan A | date = 26 March 2013 | url = https://www.newscientist.com/article/mg21729104.100-gene-therapy-cures-leukaemia-in-eight-days.html | title = Gene therapy cures leukaemia in eight days | work = The New Scientist | access-date = 15 April 2013}}</ref>

Following encouraging Phase I trials, in April, researchers announced they were starting Phase II clinical trials (called CUPID2 and SERCA-LVAD) on 250 patients<ref>{{cite web | last = Bosely | first = Sarah | date = 30 April 2013 | url = https://www.theguardian.com/science/2013/apr/30/gene-therapy-trials-heart-patients | title = Pioneering gene therapy trials offer hope for heart patients | work = The Guardian | access-date = 28 April 2014 | name-list-style = vanc }}</ref> at several hospitals to combat [[heart disease]]. The therapy was designed to increase the levels of [[SERCA]]2, a protein in heart muscles, improving muscle function.<ref>{{cite web | title=Cardiac gene therapy news: The Physicians Clinic | website=thephysiciansclinic.co.uk | date=8 September 2013 | url=https://www.thephysiciansclinic.co.uk/first-gene-therapy-trial-for-heart-failure-begins-in-uk/ | archive-url=https://web.archive.org/web/20140429053945/https://www.thephysiciansclinic.co.uk/first-gene-therapy-trial-for-heart-failure-begins-in-uk/ | archive-date=29 April 2014 | url-status=dead | access-date=2 January 2022}}</ref> The U.S. [[Food and Drug Administration]] (FDA) granted this a [[breakthrough therapy]] designation to accelerate the trial and approval process.<ref>{{cite web | title=Celladon Receives Breakthrough Therapy Designation From FDA for Mydicar, Novel, First-in-Class Therapy in Development to Treat Heart Failure | website=Celladon | date=10 July 2015 | url=http://ir.celladon.com/releasedetail.cfm?releaseid=839474 | archive-url=https://web.archive.org/web/20150710014412/http://ir.celladon.com/releasedetail.cfm?releaseid=839474 | archive-date=10 July 2015 | url-status=dead | access-date=2 January 2022}}</ref> In 2016, it was reported that no improvement was found from the CUPID 2 trial.<ref name="CUPID22016">{{cite journal | vauthors = Fernàndez-Ruiz I | title = Gene therapy: No improvement in outcomes with gene therapy for heart failure | journal = Nature Reviews. Cardiology | volume = 13 | issue = 3 | pages = 122–123 | date = March 2016 | pmid = 26843287 | doi = 10.1038/nrcardio.2016.14 | s2cid = 205472001 }}</ref>

In July researchers reported promising results for six children with two severe hereditary diseases had been treated with a partially deactivated lentivirus to replace a faulty gene and after 7–32 months. Three of the children had [[metachromatic leukodystrophy]], which causes children to lose cognitive and motor skills.<ref name="MLD">{{cite journal | vauthors = Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, Baldoli C, Martino S, Calabria A, Canale S, Benedicenti F, Vallanti G, Biasco L, Leo S, Kabbara N, Zanetti G, Rizzo WB, Mehta NA, Cicalese MP, Casiraghi M, Boelens JJ, Del Carro U, Dow DJ, Schmidt M, Assanelli A, Neduva V, Di Serio C, Stupka E, Gardner J, von Kalle C, Bordignon C, Ciceri F, Rovelli A, Roncarolo MG, Aiuti A, Sessa M, Naldini L | display-authors = 6 | title = Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy | journal = Science | volume = 341 | issue = 6148 | pages = 1233158 | date = August 2013 | pmid = 23845948 | doi = 10.1126/science.1233158 | s2cid = 206546808 | url = https://www.openaccessrepository.it/record/23020 }}</ref> The other children had [[Wiskott–Aldrich syndrome]], which leaves them to open to infection, autoimmune diseases, and cancer.<ref name="pmid23845947">{{cite journal | vauthors = Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, Dionisio F, Calabria A, Giannelli S, Castiello MC, Bosticardo M, Evangelio C, Assanelli A, Casiraghi M, Di Nunzio S, Callegaro L, Benati C, Rizzardi P, Pellin D, Di Serio C, Schmidt M, Von Kalle C, Gardner J, Mehta N, Neduva V, Dow DJ, Galy A, Miniero R, Finocchi A, Metin A, Banerjee PP, Orange JS, Galimberti S, Valsecchi MG, Biffi A, Montini E, Villa A, Ciceri F, Roncarolo MG, Naldini L | display-authors = 6 | title = Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott–Aldrich syndrome | journal = Science | volume = 341 | issue = 6148 | pages = 1233151 | date = August 2013 | pmid = 23845947 | pmc = 4375961 | doi = 10.1126/science.1233151 }}</ref> Follow up trials with gene therapy on another six children with Wiskott–Aldrich syndrome were also reported as promising.<ref>Gallagher, James (21 April 2015) [https://www.bbc.co.uk/news/health-32333161 Gene therapy: 'Tame HIV' used to cure disease] BBC News, Health, Retrieved 21 April 2015</ref><ref>{{cite journal | vauthors = Malech HL, Ochs HD | title = An emerging era of clinical benefit from gene therapy | journal = JAMA | volume = 313 | issue = 15 | pages = 1522–1523 | date = April 2015 | pmid = 25898049 | doi = 10.1001/jama.2015.2055 }}</ref>

In October researchers reported that two children born with [[Adenosine deaminase deficiency|adenosine deaminase severe combined immunodeficiency disease]] (ADA-SCID) had been treated with genetically engineered stem cells 18 months previously and that their immune systems were showing signs of full recovery. Another three children were making progress.<ref name="NewScientist1013" /> In 2014, a further 18 children with ADA-SCID were cured by gene therapy.<ref>[https://www.sciencedaily.com/releases/2014/11/141118141600.htm Gene therapy cure for children with 'bubble baby' disease]. ''Science Daily'' (18 November 2014)</ref> ADA-SCID children have no functioning immune system and are sometimes known as "bubble children".<ref name="NewScientist1013">{{cite web | last=Geddes | first=Linda | title='Bubble kid' success puts gene therapy back on track | website=New Scientist | date=30 October 2013 | url=https://www.newscientist.com/article/mg22029413-200-bubble-kid-success-puts-gene-therapy-back-on-track/ | access-date=2 January 2022 | name-list-style = vanc }}</ref>

Also in October researchers reported that they had treated six people with haemophilia in early 2011 using an adeno-associated virus. Over two years later all six were producing [[clotting factor]].<ref name="NewScientist1013" /><ref>[https://www.sciencedaily.com/releases/2014/11/141120113507.htm Gene therapy provides safe, long-term relief for patients with severe hemophilia B]. ''Science Daily'' (20 November 2014)</ref>

====2014====
In January researchers reported that six [[choroideremia]] patients had been treated with adeno-associated virus with a copy of [[Rab escort protein|REP1]]. Over a six-month to two-year period all had improved their sight.<ref name="pmid24439297">{{cite journal | vauthors = MacLaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L, Clark KR, During MJ, Cremers FP, Black GC, Lotery AJ, Downes SM, Webster AR, Seabra MC | title = Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial | journal = Lancet | volume = 383 | issue = 9923 | pages = 1129–1137 | date = March 2014 | pmid = 24439297 | pmc = 4171740 | doi = 10.1016/S0140-6736(13)62117-0 }}</ref><ref>Beali, Abigail (25 January 2014) [https://www.newscientist.com/article/dn24879-gene-therapy-restores-sight-in-people-with-eye-disease.html Gene therapy restores sight in people with eye disease] The New Scientist. Retrieved 25 January 2014</ref> By 2016, 32 patients had been treated with positive results and researchers were hopeful the treatment would be long-lasting.<ref name="BBC2016"/> Choroideremia is an inherited genetic eye disease with no approved treatment, leading to loss of sight.

In March researchers reported that 12 HIV patients had been treated since 2009 in a trial with a genetically engineered virus with a rare mutation ([[CCR5]] deficiency) known to protect against HIV with promising results.<ref>{{cite journal | vauthors = Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, Spratt SK, Surosky RT, Giedlin MA, Nichol G, Holmes MC, Gregory PD, Ando DG, Kalos M, Collman RG, Binder-Scholl G, Plesa G, Hwang WT, Levine BL, June CH | display-authors = 6 | title = Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV | journal = The New England Journal of Medicine | volume = 370 | issue = 10 | pages = 901–910 | date = March 2014 | pmid = 24597865 | pmc = 4084652 | doi = 10.1056/NEJMoa1300662 }}</ref><ref>Dvorsky, George (6 March 2014) [http://io9.com/scientists-create-genetically-modified-cells-that-prote-1537710472 Scientists Create Genetically Modified Cells That Protect Against HIV] io9, Biotechnology. Retrieved 6 March 2014</ref>

Clinical trials of gene therapy for [[sickle cell disease]] were started in 2014.<ref>{{ClinicalTrialsGov|NCT02247843|Stem Cell Gene Therapy for Sickle Cell Disease}}</ref><ref>{{ClinicalTrialsGov|NCT00012545|Collection and Storage of Umbilical Cord Stem Cells for Treatment of Sickle Cell Disease}}</ref>

In February [[LentiGlobin BB305]], a gene therapy treatment undergoing clinical trials for treatment of [[beta thalassemia]] gained FDA "breakthrough" status after several patients were able to forgo the frequent blood transfusions usually required to treat the disease.<ref>{{cite news |date=3 February 2015|title=Ten things you might have missed Monday from the world of business|url=https://www.bostonglobe.com/business/2015/02/03/ten-things-you-might-have-missed-monday-from-world-business/VlQl4rdNeHZMxWlXJJcxEK/story.html|newspaper=[[Boston Globe]]|access-date=13 February 2015 }}</ref>

In March researchers delivered a [[recombinant gene]] encoding a [[broadly neutralizing antibody]] into monkeys infected with simian [[HIV/AIDS|HIV]]; the monkeys' cells produced the [[antibody]], which cleared them of HIV. The technique is named immunoprophylaxis by gene transfer (IGT). Animal tests for antibodies to ebola, malaria, influenza, and hepatitis were underway.<ref>{{cite news|title=Protection Without a Vaccine |first= Carl |last=Zimmer | name-list-style = vanc |date=9 March 2015 |work=[[The New York Times]] |access-date=30 March 2015 |url=https://www.nytimes.com/2015/03/10/health/protection-without-a-vaccine.html |archive-url=https://ghostarchive.org/archive/20220102/https://www.nytimes.com/2015/03/10/health/protection-without-a-vaccine.html |archive-date=2 January 2022 |url-access=limited |url-status=live}}{{cbignore}}</ref><ref>{{cite journal | vauthors = Gardner MR, Kattenhorn LM, Kondur HR, von Schaewen M, Dorfman T, Chiang JJ, Haworth KG, Decker JM, Alpert MD, Bailey CC, Neale ES, Fellinger CH, Joshi VR, Fuchs SP, Martinez-Navio JM, Quinlan BD, Yao AY, Mouquet H, Gorman J, Zhang B, Poignard P, Nussenzweig MC, Burton DR, Kwong PD, Piatak M, Lifson JD, Gao G, Desrosiers RC, Evans DT, Hahn BH, Ploss A, Cannon PM, Seaman MS, Farzan M | display-authors = 6 | title = AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges | journal = Nature | volume = 519 | issue = 7541 | pages = 87–91 | date = March 2015 | pmid = 25707797 | pmc = 4352131 | doi = 10.1038/nature14264 | bibcode = 2015Natur.519...87G }}</ref>

In March, scientists, including an inventor of [[CRISPR]], [[Jennifer Doudna]], urged a worldwide moratorium on germline gene therapy, writing "scientists should avoid even attempting, in lax jurisdictions, germline genome modification for clinical application in humans" until the full implications "are discussed among scientific and governmental organizations".<ref name="NYT-20150319">{{cite news |last=Wade |first=Nicholas | name-list-style = vanc |title=Scientists Seek Ban on Method of Editing the Human Genome |url=https://www.nytimes.com/2015/03/20/science/biologists-call-for-halt-to-gene-editing-technique-in-humans.html |archive-url=https://ghostarchive.org/archive/20220102/https://www.nytimes.com/2015/03/20/science/biologists-call-for-halt-to-gene-editing-technique-in-humans.html |archive-date=2 January 2022 |url-access=limited |url-status=live |date=19 March 2015 |work=[[The New York Times]] |access-date=20 March 2015 }}{{cbignore}}</ref><ref name="NYT-20150303-AP">{{cite news |last=Pollack |first=Andrew | name-list-style = vanc |title=A Powerful New Way to Edit DNA |url=https://www.nytimes.com/2014/03/04/health/a-powerful-new-way-to-edit-dna.html |archive-url=https://ghostarchive.org/archive/20220102/https://www.nytimes.com/2014/03/04/health/a-powerful-new-way-to-edit-dna.html |archive-date=2 January 2022 |url-access=limited |url-status=live |date=3 March 2015 |work=[[The New York Times]] |access-date=20 March 2015 }}{{cbignore}}</ref><ref name="SCI-20150319">{{cite journal | vauthors = Baltimore D, Berg P, Botchan M, Carroll D, Charo RA, Church G, Corn JE, Daley GQ, Doudna JA, Fenner M, Greely HT, Jinek M, Martin GS, Penhoet E, Puck J, Sternberg SH, Weissman JS, Yamamoto KR | display-authors = 6 | title = Biotechnology. A prudent path forward for genomic engineering and germline gene modification | journal = Science | volume = 348 | issue = 6230 | pages = 36–38 | date = April 2015 | pmid = 25791083 | pmc = 4394183 | doi = 10.1126/science.aab1028 | bibcode = 2015Sci...348...36B }}</ref><ref name="NAT-20150312">{{cite journal | vauthors = Lanphier E, Urnov F, Haecker SE, Werner M, Smolenski J | title = Don't edit the human germ line | journal = Nature | volume = 519 | issue = 7544 | pages = 410–411 | date = March 2015 | pmid = 25810189 | doi = 10.1038/519410a | bibcode = 2015Natur.519..410L | doi-access = free }}</ref>

In December, scientists of major world academies called for a moratorium on inheritable [[human genome]] edits, including those related to [[Gene drive#CRISPR|CRISPR-Cas9]] technologies<ref name="NYT-20151203-nw">{{cite news |last=Wade |first=Nicholas |author-link=Nicholas Wade | name-list-style = vanc |title=Scientists Place Moratorium on Edits to Human Genome That Could Be Inherited |url=https://www.nytimes.com/2015/12/04/science/crispr-cas9-human-genome-editing-moratorium.html |archive-url=https://ghostarchive.org/archive/20220102/https://www.nytimes.com/2015/12/04/science/crispr-cas9-human-genome-editing-moratorium.html |archive-date=2 January 2022 |url-access=limited |url-status=live |date=3 December 2015 |work=[[The New York Times]] |access-date=3 December 2015 }}{{cbignore}}</ref> but that basic research including embryo gene editing should continue.<ref name="BBC31Dec">{{cite news|last1=Walsh|first1=Fergus| name-list-style = vanc |title=Gene editing: Is era of designer humans getting closer?|url=https://www.bbc.co.uk/news/health-34994180|access-date=31 December 2015|publisher=BBC News Health|date=3 December 2015}}</ref>

====2015====

Researchers successfully treated a boy with [[epidermolysis bullosa]] using skin grafts grown from his own skin cells, genetically altered to repair the mutation that caused his disease.<ref>{{Cite web|url=https://www.npr.org/2017/11/08/562647401/genetically-altered-skin-saves-a-boy-dying-of-a-rare-disease|title=Genetically Altered Skin Saves A Boy Dying Of A Rare Disease|website=NPR.org }}</ref>

In November, researchers announced that they had treated a baby girl, Layla Richards, with an experimental treatment using donor T cells genetically engineered using [[Transcription activator-like effector nuclease|TALEN]] to attack cancer cells. One year after the treatment she was still free of her cancer (a highly aggressive form of [[acute lymphoblastic leukaemia]] [ALL]).<ref>{{cite news |last=Henry |first=Robin |name-list-style=vanc |date=19 February 2017 |title=Leukaemia cure hopes rise as girl is gene‑edited |newspaper=The Times |url=http://www.thetimes.co.uk/article/leukaemia-cure-hopes-rise-as-girl-is-gene-edited-n35md6k9s |url-access=registration |access-date=20 February 2017}}</ref> Children with highly aggressive ALL normally have a very poor prognosis and Layla's disease had been regarded as terminal before the treatment.<ref name="Layla">{{cite news |last1=Sample |first1=Ian |name-list-style=vanc |date=5 November 2015 |title=Baby girl is first in the world to be treated with 'designer immune cells' |newspaper=The Guardian |url=https://www.theguardian.com/science/2015/nov/05/baby-girl-is-first-in-the-world-to-be-treated-with-designer-immune-cells |access-date=6 November 2015}}</ref><ref name=":1">{{Cite news |date=5 November 2015 |title='Designer cells' reverse one-year-old's cancer |language=en-GB |work=BBC News |url=https://www.bbc.com/news/health-34731498 |access-date=11 December 2022}}</ref>

====2016====
In April the [[Committee for Medicinal Products for Human Use]] of the [[European Medicines Agency]] endorsed a gene therapy treatment called [[Strimvelis]]<ref name="StrimvelisEMA">{{cite web|title=Summary of opinion1 (initial authorisation) Strimvelis| url=http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/003854/WC500203918.pdf| website=European Medicines Agency|access-date=13 April 2016|ref=EMA/CHMP/160482/2016|pages=1–2|date=1 April 2016}}</ref><ref name="Hirscheler">{{cite news|last1=Hirscheler|first1=Ben| name-list-style = vanc |title=Europe gives green light to first gene therapy for children|url=http://www.reuters.com/article/us-health-genetherapy-gsk-idUKKCN0WY4XF|access-date=13 April 2016|work=Reuters|date=1 April 2016}}</ref> and the European Commission approved it in June.<ref>{{cite web|url=http://www.bionews.org.uk/page_656359.asp|title=Second gene therapy wins approval in Europe|last=Reeves|first=Rachel| name-list-style = vanc |date=6 June 2016|website=Bionews|access-date=20 February 2017}}</ref> This treats children born with [[adenosine deaminase deficiency]] and who have no functioning immune system. This was the second gene therapy treatment to be approved in Europe.<ref name="Strimvelis">{{cite magazine|last1=Coghlan|first1=Andy| name-list-style = vanc |title=Gene Therapy Approved|url=https://www.newscientist.com/article/2083180-gene-therapy-gets-approval-for-bubble-kids-in-world-first/|issue=3068|magazine= New Scientist|date=9 April 2016|pages=8–9}}</ref>

In October, Chinese scientists reported they had started a trial to genetically modify T cells from 10 adult patients with lung cancer and reinject the modified T cells back into their bodies to attack the cancer cells. The T cells had the [[Programmed cell death protein 1|PD-1 protein]] (which stops or slows the immune response) removed using CRISPR-Cas9.<ref>{{cite journal | vauthors = Cyranoski D | title = Chinese scientists to pioneer first human CRISPR trial | journal = Nature | volume = 535 | issue = 7613 | pages = 476–477 | date = July 2016 | pmid = 27466105 | doi = 10.1038/nature.2016.20302 | bibcode = 2016Natur.535..476C | doi-access = free }}</ref><ref>{{cite news | first = Jay | last = Bennett | name-list-style = vanc | url = http://www.popularmechanics.com/science/health/a23898/crispr-gene-editing-tool-used-on-a-human/ | title = Chinese Scientists Become First to Use CRISPR Gene-Editing on Humans | date = 15 November 2016 | newspaper = Popular Mechanics |access-date = 16 November 2016 }}</ref>

A 2016 [[Cochrane (organisation)|Cochrane systematic review]] looking at data from four trials on [[Cystic fibrosis transmembrane conductance regulator|topical cystic fibrosis transmembrane conductance regulator]] (CFTR) gene therapy does not support its clinical use as a mist inhaled into the lungs to treat cystic fibrosis patients with lung infections. One of the four trials did find weak evidence that liposome-based CFTR gene transfer therapy may lead to a small respiratory improvement for people with CF. This weak evidence is not enough to make a clinical recommendation for routine CFTR gene therapy.<ref>{{cite journal |vauthors=Lee TW, Southern KW, Perry LA, Penny-Dimri JC, Aslam AA | editor1-first = Kevin W | editor1-last = Southern | title = Topical cystic fibrosis transmembrane conductance regulator gene replacement for cystic fibrosis-related lung disease | journal = The Cochrane Database of Systematic Reviews | issue = 6 | pages = CD005599 | date = June 2016 | volume = 2016 | pmid = 27314455 | doi = 10.1002/14651858.CD005599.pub5 | pmc = 8682957 | name-list-style = vanc }}</ref>

==== 2017 ====
In February [[Kite Pharma]] announced results from a clinical trial of [[CAR-T]] cells in around a hundred people with advanced [[non-Hodgkin lymphoma]].<ref>{{cite news|url=http://www.thetimes.co.uk/article/new-gene-therapy-offers-hope-for-cancer-patients-dl2m7zmzs|title=New gene therapy 'shrinks tumours like ice cubes'|last=Whipple|first=Tom| name-list-style = vanc |date=1 March 2017|work=The Times|access-date=1 March 2017|url-access=subscription }}</ref>

In March, French scientists reported on clinical research of gene therapy to treat [[sickle cell disease]].<ref>{{cite magazine | url = https://www.newscientist.com/article/mg23331154-800-gene-therapy-breakthrough/ | title=Gene therapy 'cures' boy of blood disease that affects millions | last = Coghlan | first = Andy | name-list-style = vanc | date= March 2017 | magazine = New Scientist }}</ref>

In August, the FDA approved [[tisagenlecleucel]] for [[acute lymphoblastic leukemia]].<ref>{{cite press release | title = FDA approval brings first gene therapy to the United States | publisher = U.S. [[Food and Drug Administration]] (FDA) | date = 30 August 2017| url = https://www.fda.gov/news-events/press-announcements/fda-approval-brings-first-gene-therapy-united-states }}</ref> Tisagenlecleucel is an [[adoptive cell transfer]] therapy for [[B-cell]] acute lymphoblastic leukemia; [[T cells]] from a person with cancer are removed, [[genetically engineered]] to make a specific [[T-cell receptor]] (a chimeric T cell receptor, or "CAR-T") that reacts to the cancer, and are administered back to the person. The T cells are engineered to target a protein called [[CD19]] that is common on B cells. This is the first form of gene therapy to be approved in the United States. In October, a similar therapy called [[axicabtagene ciloleucel]] was approved for non-Hodgkin lymphoma.<ref>{{cite web|url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-axicabtagene-ciloleucel-large-b-cell-lymphoma |title=FDA approves axicabtagene ciloleucel for large B-cell lymphoma|website=U.S. [[Food and Drug Administration]] (FDA)|access-date=5 January 2018}}</ref>

In October, [[Biophysics|biophysicist]] and [[Do-it-yourself biology|biohacker]] [[Josiah Zayner]] claimed to have performed the very first in-vivo human genome editing in the form of a self-administered therapy.<ref>{{cite web|last=Zayner|first=Josiah|date=6 October 2017|title=DIY Human CRISPR Myostatin Knock-Out|url=https://www.youtube.com/watch?v=o6A9bbDI6fo&| archive-url=https://web.archive.org/web/20171111130250/https://www.youtube.com/watch?v=o6A9bbDI6fo| archive-date=11 November 2017 | url-status=dead|access-date=20 May 2020|website=Youtube}}</ref><ref>{{cite web|last=Zayner|first=Josiah|title=The First Attempt At Human CRISPR Gene Editing|url=http://www.josiahzayner.com/2017/10/the-first-human-to-attempt-crispr-gene.html|access-date=20 May 2020}}</ref>

On 13 November, medical scientists working with [[Sangamo Therapeutics]], headquartered in [[Richmond, California]], announced the first ever in-body [[human gene editing therapy]].<ref>{{cite web|title=AP Exclusive: US scientists try 1st gene editing in the body|url=https://apnews.com/article/4ae98919b52e43d8a8960e0e260feb0a|access-date=17 November 2020|website=AP NEWS}}</ref><ref>{{cite journal|last1=Kaiser |first1=Jocelyn |date=November 2017|title=A human has been injected with gene-editing tools to cure his disabling disease. Here's what you need to know |journal=Science | doi=10.1126/science.aar5098 | doi-access=free | title-link=doi | name-list-style = vanc }}</ref> The treatment, designed to permanently insert a healthy version of the flawed gene that causes [[Hunter syndrome]], was given to 44-year-old Brian Madeux and is part of the world's first study to permanently edit [[DNA]] inside the human body.<ref>{{cite web|last=Zhang|first=Sarah|date=15 November 2017|title=The First Man to Have His Genes Edited Inside His Body|url=https://www.theatlantic.com/science/archive/2017/11/sangamo-first-gene-editing-in-body/545960/|access-date=17 November 2020|website=The Atlantic}}</ref> The success of the gene insertion was later confirmed.<ref>{{cite journal|last=Ledford|first=Heidi|date=5 September 2018|title=First test of in-body gene editing shows promise|journal=Nature|doi=10.1038/d41586-018-06195-6|s2cid=92840885| doi-access=free | title-link=doi }}</ref><ref name="AP-20190207">{{cite news|last=Marchione|first=Marilyn|date=7 February 2019|title=Tests suggest scientists achieved 1st 'in body' gene editing|work=[[AP News]]|url=https://www.apnews.com/d728f86d70d94ce68dd4fedffe58d03f|access-date=7 February 2019}}</ref> Clinical trials by Sangamo involving gene editing using [[zinc finger nuclease]] (ZFN) are ongoing.<ref name="CT-201902">{{cite web|author=Staff|date=2 February 2019|title=Ascending Dose Study of Genome Editing by the Zinc Finger Nuclease (ZFN) Therapeutic SB-913 in Subjects With MPS II|url=https://clinicaltrials.gov/ct2/show/NCT03041324|access-date=7 February 2019|website=[[ClinicalTrials.gov]]|publisher=[[U.S. National Library of Medicine]]}}</ref>

In December the results of using an adeno-associated virus with blood clotting [[factor VIII]] to treat nine [[haemophilia A]] patients were published. Six of the seven patients on the high dose regime increased the level of the blood clotting VIII to normal levels. The low and medium dose regimes had no effect on the patient's blood clotting levels.<ref>{{cite journal | vauthors = Rangarajan S, Walsh L, Lester W, Perry D, Madan B, Laffan M, Yu H, Vettermann C, Pierce GF, Wong WY, Pasi KJ | title = AAV5-Factor VIII Gene Transfer in Severe Hemophilia A | display-authors = 6 | journal = The New England Journal of Medicine | volume = 377 | issue = 26 | pages = 2519–2530 | date = December 2017 | pmid = 29224506 | doi = 10.1056/nejmoa1708483 | hdl = 10044/1/57163 | doi-access = free }}</ref><ref>{{cite journal | vauthors = van den Berg HM | title = A Cure for Hemophilia within Reach | journal = The New England Journal of Medicine | volume = 377 | issue = 26 | pages = 2592–2593 | date = December 2017 | pmid = 29224412 | doi = 10.1056/nejme1713888 }}</ref>

In December, the FDA approved [[Luxturna]], the first ''in vivo'' gene therapy, for the treatment of blindness due to [[Leber's congenital amaurosis]].<ref>{{cite press release|url=https://www.fda.gov/news-events/press-announcements/fda-approves-novel-gene-therapy-treat-patients-rare-form-inherited-vision-loss |title=FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss|date=19 December 2017|website=U.S. [[Food and Drug Administration]] (FDA)|access-date=20 December 2017}}</ref> The price of this treatment is {{US$|850,000}} for both eyes.<ref>{{cite news|url=https://www.forbes.com/sites/matthewherper/2018/01/03/spark-therapeutics-sets-price-of-blindness-curing-gene-therapy-at-850000/|title=Spark Therapeutics Sets Price Of Blindness-Treating Gene Therapy At $850,000|last=Herper|first=Matthew|date=2 January 2018|work=Forbes|access-date=4 January 2018}}</ref><ref>{{cite news|url=http://www.newsweek.com/groundbreaking-approval-fda-signs-first-ever-gene-therapy-752711|title=The FDA approved a gene therapy to treat blindness in a groundbreaking moment for DNA-based medicine|last=Sheridan|first=Kate| name-list-style = vanc |date=19 December 2017|work=Newsweek|access-date=20 December 2017}}</ref>

==== 2019 ====
In May, the FDA approved [[onasemnogene abeparvovec]] (Zolgensma) for treating [[spinal muscular atrophy]] in children under two years of age. The list price of Zolgensma was set at {{US$|2.125 million}} per dose, making it the most expensive drug ever.<ref>{{cite news |last1=Stein |first1=Rob |title=At $2.1 Million, New Gene Therapy Is The Most Expensive Drug Ever |url=https://www.npr.org/sections/health-shots/2019/05/24/725404168/at-2-125-million-new-gene-therapy-is-the-most-expensive-drug-ever |access-date=24 May 2019 |work=[[NPR]] |date=24 May 2019 | name-list-style = vanc }}</ref>

In May, the EMA approved [[betibeglogene autotemcel]] (Zynteglo) for treating [[beta thalassemia]] for people twelve years of age and older.<ref>{{cite news |last1=Tong |first1=Amber | title =EU stamps historic OK on bluebird's gene therapy for β-thalassemia – now sit back and wait for the price |url=https://endpts.com/eu-stamps-historic-ok-on-bluebirds-gene-therapy-for-%CE%B2-thalassemia-now-sit-back-and-wait-for-the-price/ | access-date=4 June 2019 |date=3 June 2019 | name-list-style = vanc }}</ref><ref name="Zynteglo EPAR">{{cite web |title=Zynteglo EPAR |url=https://www.ema.europa.eu/en/medicines/human/EPAR/zynteglo |website=[[European Medicines Agency]] (EMA) |access-date=8 June 2020}} Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>

In July, [[Allergan]] and [[Editas Medicine]] announced phase I/II clinical trial of AGN-151587 for the treatment of [[Leber congenital amaurosis]] 10.<ref>{{cite web |title=Single Ascending Dose Study in Participants With LCA10 |url=https://clinicaltrials.gov/ct2/show/NCT03872479 |website=clinicaltrials.gov |access-date=20 August 2019 }}</ref> This is the first study of a [[CRISPR]]-based ''[[in vivo]]'' [[human gene editing therapy]], where the editing takes place inside the human body.<ref>{{cite web |title=Allergan and Editas Medicine Initiate the Brilliance Phase 1/2 Clinical Trial of AGN-151587 (EDIT-101) for the Treatment of LCA10 |url=http://ir.editasmedicine.com/news-releases/news-release-details/allergan-and-editas-medicine-initiate-brilliance-phase-12 |website=Editas Medicine |access-date=20 August 2019 }}</ref> The first injection of the CRISPR-Cas System was confirmed in March 2020.<ref>{{cite journal|last=Ledford|first=Heidi|date=5 March 2020|title=CRISPR treatment inserted directly into the body for first time|journal=Nature|volume=579|issue=7798|pages=185|doi=10.1038/d41586-020-00655-8|pmid=32157225|bibcode=2020Natur.579..185L|doi-access=free}}</ref>

=== 2020s ===

==== 2020 ====
In May, onasemnogene abeparvovec (Zolgensma) was approved by the European Union for the treatment of spinal muscular atrophy in people who either have clinical symptoms of SMA type 1 or who have no more than three copies of the [[SMN2|''SMN2'' gene]], irrespective of body weight or age.<ref name="Zolgensma EPAR">{{cite web | title=Zolgensma EPAR | website=[[European Medicines Agency]] (EMA) | url=https://www.ema.europa.eu/en/medicines/human/EPAR/zolgensma | access-date=16 October 2020}}</ref>

In August, [[Astellas Pharma|Audentes Therapeutics]] reported that three out of 17 children with [[X-linked myotubular myopathy]] participating the clinical trial of a AAV8-based gene therapy treatment AT132 have died. It was suggested that the treatment, whose dosage is based on body weight, exerts a disproportionately toxic effect on heavier patients, since the three patients who died were heavier than the others.<ref>{{cite web|date=10 August 2020|title=Audentes Therapeutics Provides Update on the ASPIRO Clinical Trial Evaluating AT132 in Patients with X-linked Myotubular Myopathy|url=https://www.audentestx.com/press_release/audentes-therapeutics-provides-update-on-the-aspiro-clinical-trial-evaluating-at132-in-patients-with-x-linked-myotubular-myopathy/|access-date=21 September 2020|website=Audentes Therapeutics}}</ref><ref>{{cite web|title=Astellas' Audentes reports 3rd death in gene therapy trial|url=https://www.fiercebiotech.com/biotech/astellas-audentes-reports-third-death-gene-therapy-trial|access-date=21 September 2020|website=FierceBiotech|date=21 August 2020}}</ref> The trial has been put on clinical hold.<ref>{{cite journal|date=1 August 2020|title=High-dose AAV gene therapy deaths|journal=Nature Biotechnology|volume=38|issue=8|pages=910|doi=10.1038/s41587-020-0642-9|pmid=32760031|s2cid=220981004|issn=1546-1696|doi-access=free}}</ref>

On 15 October, the [[Committee for Medicinal Products for Human Use]] (CHMP) of the [[European Medicines Agency]] (EMA) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product [[Libmeldy]] (autologous CD34+ cell enriched population that contains hematopoietic stem and progenitor cells transduced ex vivo using a lentiviral vector encoding the human arylsulfatase A gene), a gene therapy for the treatment of children with the "late infantile" (LI) or "early juvenile" (EJ) forms of metachromatic leukodystrophy (MLD).<ref name="Libmeldy: Pending EC decision">{{cite web | title=Libmeldy: Pending EC decision | website=[[European Medicines Agency]] (EMA) | date=16 October 2020 | url=https://www.ema.europa.eu/en/medicines/human/summaries-opinion/libmeldy | access-date=16 October 2020}} Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> The active substance of Libmeldy consists of the child's own stem cells which have been modified to contain working copies of the ARSA gene.<ref name="Libmeldy: Pending EC decision" /> When the modified cells are injected back into the patient as a one-time infusion, the cells are expected to start producing the ARSA enzyme that breaks down the build-up of sulfatides in the nerve cells and other cells of the patient's body.<ref name="EMA PR">{{cite web|date=16 October 2020|title=New gene therapy to treat rare genetic disorder metachromatic leukodystrophy|url=https://www.ema.europa.eu/en/news/new-gene-therapy-treat-rare-genetic-disorder-metachromatic-leukodystrophy|access-date=16 October 2020|website=European Medicines Agency}} Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> Libmeldy was approved for medical use in the EU in December 2020.<ref name="Libmeldy EPAR">{{cite web | title=Libmeldy EPAR | website=[[European Medicines Agency]] (EMA) | url=https://www.ema.europa.eu/en/medicines/human/EPAR/libmeldy | access-date=22 December 2020}}</ref>

On 15 October, Lysogene, a French biotechnological company, reported the death of a patient in who has received LYS-SAF302, an experimental gene therapy treatment for [[Sanfilippo syndrome|mucopolysaccharidosis type IIIA]] (Sanfilippo syndrome type A).<ref>{{cite web|last=Lysogene|title=Lysogene provides update on the AAVance Clinical Trial Evaluating LYS-SAF302 in Patients with MPS IIIA – Lysogene|date=15 October 2020|url=https://www.lysogene.com/lysogene-provides-update-on-the-aavance-clinical-trial-evaluating-lys-saf302-in-patients-with-mps-iiia/|access-date=17 October 2020}}</ref>

====2021====

In May, a new method using an altered version of the [[HIV]] virus as a [[Viral vector#Lentiviruses|lentivirus vector]] was reported in the treatment of 50 children with ADA-SCID obtaining positive results in 48 of them,<ref>{{cite journal|last1=Kohn|first1=Donald B.|last2=Booth|first2=Claire|last3=Shaw|first3=Kit L.|last4=Xu-Bayford|first4=Jinhua|last5=Garabedian|first5=Elizabeth|last6=Trevisan|first6=Valentina|last7=Carbonaro-Sarracino|first7=Denise A.|last8=Soni|first8=Kajal|last9=Terrazas|first9=Dayna|last10=Snell|first10=Katie|last11=Ikeda|first11=Alan | display-authors=6 |date=May 2021|title=Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency|journal=New England Journal of Medicine|volume=384|issue=21|pages=2002–2013|doi=10.1056/NEJMoa2027675|pmc=8240285|pmid=33974366 | doi-access=free | title-link=doi | name-list-style = vanc }}</ref><ref>{{cite web|last=says|first=Chris|date=11 May 2021|title=AIDS virus used in gene therapy to fix 'bubble baby' disease|url=https://www.statnews.com/2021/05/11/aids-virus-used-in-gene-therapy-to-fix-bubble-baby-disease/|access-date=19 July 2021|website=[[Stat (website)|Stat]]}}</ref><ref>{{cite web|date=11 May 2021|title=Gene therapy restores immune function in children with rare immunodeficiency|url=https://www.nih.gov/news-events/news-releases/gene-therapy-restores-immune-function-children-rare-immunodeficiency|access-date=19 July 2021|website=National Institutes of Health (NIH)}}</ref> this method is expected to be safer than [[Viral vector#Retroviruses|retroviruses vectors]] commonly used in previous studies of SCID where the development of [[leukemia]] was usually observed<ref>{{cite web|title=Why Gene Therapy Caused Leukemia In Some 'Boy In The Bubble Syndrome' Patients|url=https://www.sciencedaily.com/releases/2008/08/080807175438.htm|access-date=19 July 2021|website=ScienceDaily}}</ref> and had already been used in 2019, but in a smaller group with X-SCID.<ref>{{cite journal|last1=Mamcarz|first1=Ewelina|last2=Zhou|first2=Sheng|last3=Lockey|first3=Timothy|last4=Abdelsamed|first4=Hossam|last5=Cross|first5=Shane J.|last6=Kang|first6=Guolian|last7=Ma|first7=Zhijun|last8=Condori|first8=Jose|last9=Dowdy|first9=Jola|last10=Triplett|first10=Brandon|last11=Li|first11=Chen | display-authors=6 |date=April 2019|title=Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1|journal=New England Journal of Medicine|volume=380|issue=16|pages=1525–1534|doi=10.1056/NEJMoa1815408|pmc=6636624|pmid=30995372 | doi-access=free | title-link=doi | name-list-style = vanc }}</ref><ref>{{cite news|date=17 April 2019|title=HIV used to cure 'bubble boy' disease|work=BBC News|url=https://www.bbc.com/news/world-us-canada-47969367|access-date=19 July 2021}}</ref><ref>{{cite web|last=Pittman|first=Jessica Ravitz,John David|title=These Scientists May Have Found a Cure for 'Bubble Boy' Disease|url=https://www.smithsonianmag.com/science-nature/scientists-found-cure-bubble-boy-disease-180973496/|access-date=19 July 2021|website=Smithsonian Magazine}}</ref><ref name=":02">{{cite web|last=Rohr|first=Karen|date=17 April 2019|title=Gene therapy restores immunity in infants with rare immunodeficiency disease|url=https://www.nih.gov/news-events/news-releases/gene-therapy-restores-immunity-infants-rare-immunodeficiency-disease|access-date=4 June 2020|website=National Institutes of Health (NIH)}}</ref>

In June a clinical trial on six patients affected with [[Familial amyloid polyneuropathy|transthyretin amyloidosis]] reported a reduction the concentration of missfolded [[Transthyretin|transthretin]] (TTR) protein in serum through [[CRISPR gene editing|CRISPR]]-based inactivation of the ''TTR'' gene in liver cells observing mean reductions of 52% and 87% among the lower and higher dose groups.This was done in vivo without taking cells out of the patient to edit them and reinfuse them later.<ref>{{cite journal|last1=Gillmore|first1=Julian D.|last2=Gane|first2=Ed|last3=Taubel|first3=Jorg|last4=Kao|first4=Justin|last5=Fontana|first5=Marianna|last6=Maitland|first6=Michael L.|last7=Seitzer|first7=Jessica|last8=O'Connell|first8=Daniel|last9=Walsh|first9=Kathryn R.|last10=Wood|first10=Kristy|last11=Phillips|first11=Jonathan | display-authors=6 |date=August 2021|title=CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis|journal=New England Journal of Medicine|volume=385|issue=6|pages=493–502|doi=10.1056/NEJMoa2107454|pmid=34215024|s2cid=235722446 |url=https://discovery.ucl.ac.uk/id/eprint/10133469/| name-list-style = vanc }}</ref><ref>{{cite web|title=News: Clinical Trial Update: Positive Data for First Ever In Vivo CRISPR Medicine|url=https://crisprmedicinenews.com/news/clinical-trial-update-positive-data-for-first-ever-in-vivo-crispr-medicine/|access-date=16 December 2021|website=CRISPR Medicine}}</ref><ref>{{cite journal|date=14 December 2021|title=The science news that shaped 2021: Nature's picks|journal=Nature|doi=10.1038/d41586-021-03734-6|pmid=34907370|s2cid=245144020}}</ref>

In July results of a small gene therapy [[Phases of clinical research#Phase I|phase I]] study was published reporting observation of dopamine restoration on seven patients between 4 and 9 years old affected by [[aromatic L-amino acid decarboxylase deficiency]] (AADC deficiency).<ref>{{cite journal|last1=Pearson|first1=Toni S.|last2=Gupta|first2=Nalin|last3=San Sebastian|first3=Waldy|last4=Imamura-Ching|first4=Jill|last5=Viehoever|first5=Amy|last6=Grijalvo-Perez|first6=Ana|last7=Fay|first7=Alex J.|last8=Seth|first8=Neha|last9=Lundy|first9=Shannon M.|last10=Seo|first10=Youngho|last11=Pampaloni|first11=Miguel | display-authors=6 |date=July 2021|title=Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons|journal=Nature Communications|volume=12|issue=1|pages=4251|doi=10.1038/s41467-021-24524-8|pmid=34253733|issn=2041-1723|pmc=8275582|bibcode=2021NatCo..12.4251P | name-list-style = vanc }}</ref><ref>{{cite journal|last1=Ibrahim |first1=Mennatalla |date=14 July 2021|title=Gene therapy restores missing dopamine in children with rare brain disease|url=https://www.science.org/content/article/gene-therapy-restores-missing-dopamine-children-rare-brain-disease|access-date=18 July 2021|journal=Science | name-list-style = vanc }}</ref><ref>{{cite web|date=12 July 2021|title=Gene therapy trial points to a wider window to alter course of rare disease|url=https://www.statnews.com/2021/07/12/gene-therapy-aadc-deficiency/|access-date=18 July 2021|website=[[Stat (website)|Stat]]}}</ref>

====2022====
In February, the first ever gene therapy for [[Tay–Sachs disease]] was announced, it uses an [[adeno-associated virus]] to deliver the correct instruction for the [[HEXA]] gene on brain cells which causes the disease. Only two children were part of a compassionate trial presenting improvements over the natural course of the disease and no vector-related [[adverse event]]s.<ref>{{Cite journal |last1=Flotte |first1=Terence R. |last2=Cataltepe |first2=Oguz |last3=Puri |first3=Ajit |last4=Batista |first4=Ana Rita |last5=Moser |first5=Richard |last6=McKenna-Yasek |first6=Diane |last7=Douthwright |first7=Catherine |last8=Gernoux |first8=Gwladys |last9=Blackwood |first9=Meghan |last10=Mueller |first10=Christian |last11=Tai |first11=Phillip W. L. |date=10 February 2022 |title=AAV gene therapy for Tay-Sachs disease |url=https://www.nature.com/articles/s41591-021-01664-4 |journal=Nature Medicine |language=en |volume=28 |issue=2 |pages=251–259 |doi=10.1038/s41591-021-01664-4 |pmid=35145305 |s2cid=246748772 |issn=1078-8956}}</ref><ref>{{Cite web |last=Sena-Esteves |first=Miguel |date=14 February 2022|title=First gene therapy for Tay-Sachs disease successfully given to two children |url=http://theconversation.com/first-gene-therapy-for-tay-sachs-disease-successfully-given-to-two-children-176870 |access-date=7 March 2022 |website=The Conversation}}</ref><ref>{{Cite web |date=18 February 2022 |title=Parents spark breakthrough gene therapy for children with Tay-Sachs disease |url=https://www.independent.co.uk/news/world/americas/taysachs-gene-therapy-b2017038.html |access-date=7 March 2022 |website=The Independent}}</ref>

In May, [[eladocagene exuparvovec]] is recommended for approval by the European Commission.<ref name="Upstaza: Pending EC decision">{{cite web | title=Upstaza: Pending EC decision | website=European Medicines Agency | date=19 May 2022 | url=https://www.ema.europa.eu/en/medicines/human/summaries-opinion/upstaza | access-date=22 May 2022}}</ref><ref name="PTC PR 20220520">{{cite press release | title=PTC Therapeutics Receives Positive CHMP Opinion for Upstaza for the Treatment of AADC Deficiency | website=[[PTC Therapeutics]] | date=20 May 2022 | url=https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-receives-positive-chmp-opinion-upstazatm | access-date=22 May 2022}}</ref>

In July results of a gene therapy candidate for [[haemophilia B]] called  FLT180 were announced, it works using an [[adeno-associated virus]] (AAV) to restore the clotting [[factor IX]] (FIX) protein, normal levels of the protein were observed with low doses of the therapy but immunosuppression was necessitated to decrease the risk of vector-related immune responses.<ref>{{Cite journal |last1=Chowdary |first1=Pratima |last2=Shapiro |first2=Susan |last3=Makris |first3=Mike |last4=Evans |first4=Gillian |last5=Boyce |first5=Sara |last6=Talks |first6=Kate |last7=Dolan |first7=Gerard |last8=Reiss |first8=Ulrike |last9=Phillips |first9=Mark |last10=Riddell |first10=Anne |last11=Peralta |first11=Maria R. |date=21 July 2022 |title=Phase 1–2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B |url=https://doi.org/10.1056/NEJMoa2119913 |journal=New England Journal of Medicine |volume=387 |issue=3 |pages=237–247 |doi=10.1056/NEJMoa2119913 |pmid=35857660 |s2cid=250697905 |issn=0028-4793}}</ref><ref>{{Cite web |title=Novel gene therapy could reduce bleeding risk for haemophilia patients |url=https://www.sciencedaily.com/releases/2022/07/220720193711.htm |access-date=3 August 2022 |website=ScienceDaily |language=en}}</ref><ref>{{Cite news |date=21 July 2022 |title=Transformational therapy cures haemophilia B |language=en-GB |work=BBC News |url=https://www.bbc.com/news/health-62240061 |access-date=3 August 2022}}</ref>

In December, a 13-year girl that had been diagnosed with [[T-cell acute lymphoblastic leukemia|T-cell acute lymphoblastic leukaemia]] was successfully treated at [[Great Ormond Street Hospital]] (GOSH) in the first documented use of therapeutic gene editing for this purpose, after undergoing six months of an experimental treatment, where all attempts of other treatments failed. The procedure included reprogramming a healthy T-cell to destroy the cancerous T-cells to first rid her of leukaemia, and then rebuilding her immune system using healthy immune cells.<ref>{{cite news| title=Base editing: Revolutionary therapy clears girl's incurable cancer | website=BBC News | date=11 December 2022 | url=https://www.bbc.co.uk/news/health-63859184 | access-date = 11 December 2022}}</ref> The GOSH team used [[Genome_editing#Editing by Nucleobase Modification (BASE_Editing)|BASE editing]] and had [[Gene therapy#2015|previously]] treated a case of [[acute lymphoblastic leukaemia]] in 2015 using [[TALENs]].<ref name=":1" />

== References ==
{{Reflist}}

== Further reading ==
* {{cite web | vauthors = Tinkov S, Bekeredjian R, Winter G, Coester C | title = Polyplex-conjugated microbubbles for enhanced ultrasound targeted gene therapy | publisher = 2008 AAPS Annual Meeting and Exposition | date = 20 November 2000 | location = [[Georgia World Congress Center]], Atlanta, GA | url = http://www.aapsj.org/abstracts/AM_2008/AAPS2008-000838.PDF | access-date = 26 January 2009 | archive-url = https://web.archive.org/web/20120707180351/http://www.aapsj.org/abstracts/AM_2008/AAPS2008-000838.PDF | archive-date = 7 July 2012 | url-status = dead }}
* {{cite journal | vauthors = Gardlík R, Pálffy R, Hodosy J, Lukács J, Turna J, Celec P | title = Vectors and delivery systems in gene therapy | journal = Medical Science Monitor | volume = 11 | issue = 4 | pages = RA110–121 | date = April 2005 | pmid = 15795707 }}
* {{cite web | last = Staff|date= 18 November 2005 | url = http://www.ornl.gov/sci/techresources/Human_Genome/medicine/genetherapy.shtml | title = Gene Therapy| format = FAQ| work = Human Genome Project Information | publisher = [[Oak Ridge National Laboratory]] | access-date = 28 May 2006|archive-url=https://web.archive.org/web/20060427174645/http://www.ornl.gov/sci/techresources/Human_Genome/medicine/genetherapy.shtml|archive-date=27 April 2006|url-status=dead | name-list-style = vanc }}
* {{cite journal | vauthors = Salmons B, Günzburg WH | title = Targeting of retroviral vectors for gene therapy | journal = Human Gene Therapy | volume = 4 | issue = 2 | pages = 129–141 | date = April 1993 | pmid = 8494923 | doi = 10.1089/hum.1993.4.2-129 }}
* {{cite journal | vauthors = Baum C, Düllmann J, Li Z, Fehse B, Meyer J, Williams DA, von Kalle C | title = Side effects of retroviral gene transfer into hematopoietic stem cells | journal = Blood | volume = 101 | issue = 6 | pages = 2099–2114 | date = March 2003 | pmid = 12511419 | doi = 10.1182/blood-2002-07-2314 | s2cid = 8489829 }}
* {{cite journal | vauthors = Horn PA, Morris JC, Neff T, Kiem HP | title = Stem cell gene transfer – efficacy and safety in large animal studies | journal = Molecular Therapy | volume = 10 | issue = 3 | pages = 417–431 | date = September 2004 | pmid = 15336643 | doi = 10.1016/j.ymthe.2004.05.017 | doi-access = free }}
* {{cite journal | vauthors = Wang H, Shayakhmetov DM, Leege T, Harkey M, Li Q, Papayannopoulou T, Stamatoyannopolous G, Lieber A | title = A capsid-modified helper-dependent adenovirus vector containing the beta-globin locus control region displays a nonrandom integration pattern and allows stable, erythroid-specific gene expression | journal = Journal of Virology | volume = 79 | issue = 17 | pages = 10999–11013 | date = September 2005 | pmid = 16103151 | pmc = 1193620 | doi = 10.1128/JVI.79.17.10999-11013.2005 }}
* {{cite journal | title=Gene Therapy: An Overview of Approved and Pipeline Technologies | journal=CADTH | url=https://cadth.ca/sites/default/files/pdf/eh0068_gene_therapy.pdf |archive-url=https://web.archive.org/web/20181019222316/https://www.cadth.ca/sites/default/files/pdf/eh0068_gene_therapy.pdf |archive-date=19 October 2018 |url-status=live | issue=171 | date=March 2018 }}
* Gorell, E., Nguyen, N., Lane, A., & Siprashvili, Z. (2014). Gene therapy for skin diseases. Cold Spring Harbor perspectives in medicine, 4(4), a015149. [https://doi.org/10.1101/cshperspect.a015149 Gene Therapy for Skin Diseases]
* {{cite journal | vauthors = Parambi DG, Alharbi KS, Kumar R, Harilal S, Batiha GE, Cruz-Martins N, Magdy O, Musa A, Panda DS, Mathew B | title = Gene Therapy Approach with an Emphasis on Growth Factors: Theoretical and Clinical Outcomes in Neurodegenerative Diseases | journal = Molecular Neurobiology | date = October 2021 | volume = 59 | issue = 1 | pages = 191–233 | pmid = 34655056 | pmc = 8518903 | doi = 10.1007/s12035-021-02555-y }}

== External links ==
{{wikibooks|Genes, Technology and Policy}}
{{commons}}
* [https://www.scientificamerican.com/article/gene-therapy-arrives/ Commercial gene therapies produced by 2020]

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