What is gene therapy?

Evolution of Gene Therapy

Though only a small number of gene therapies are currently approved for use, gene therapy is not a new approach to treating diseases. As you’ll see in this part of genehome, many years of scientific and clinical research have led us to the world of gene therapy today.

Shaping gene therapy

Researchers specializing in genetic diseasesa disease caused by a mutation (or problem) in one or more genes

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have asked themselves the same question for decades: What if we could treat an inherited disease or cancer at the genetic level?

Most researchers believed Gene therapya method of treating genetic diseases at the genetic level (the source) with the goal of changing the course of a disease

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was possible from the beginning. But it has taken decades of hard work and learning to better understand genetics and discover techniques with the potential to treat inherited diseases and cancers at the genetic level.1 

In recent years, gene therapy has taken major strides forward. Now, it continues to advance from research into the pipeline for US Food and Drug Administration (FDA)an agency in the US federal government whose mission is to protect public health by making sure that drugs, medical devices, and other equipment are safe and effective

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 review and potential approvals, with the ultimate goal of serving the patient populations who may benefit.2
Image of gene mapping
Gene-ius Questions
Gene therapy was not discovered by one individual. Instead, it was the research of many individuals that has contributed to the understanding of gene therapy that we have today.
History of gene therapy

Gene therapy has evolved over the years. Here are some of the most important milestones that have brought us to where we are with gene therapy today: 

1953

 

The structure of DNA was characterized by a double helix3

King’s College London

 

1961-1966

The genetic code was discovered by deciphering the three bases of DNA in 1 of the 20 amino acids. The 19 remaining amino acids were deciphered soon after, paving the way for new technologies4

National Institutes of Health (NIH)

1973

 

 

Researchers discovered a genetic engineering technique that allows genetic material from 1 organism to be artificially introduced, replicated, and expressed in another5

  • DNA was spliced into a plasmid carrier (a DNA structure that can replicate without a chromosome), which then inserted genetic material into an E. coli bacterium. When the bacterium reproduced, it replicated the foreign DNA and maintained the genetic material from the original organism

US-Japan joint meeting on plasmids, Hawaii

1980

One of the first times gene therapy was tested in people was done without permission from the university who provided funding or the National Institutes of Health (NIH). The researcher lost multiple grants and NIH warned others that human experimentation would not be tolerated6

  • Martin Cline attempted gene therapy abroad without permission in 2 patients with beta-thalassemia, a rare inherited blood disorder, by transferring the beta-globin gene into their cells. This did not work because the cells did not replicate.

The University of California, Los Angeles

1990

The first gene therapy clinical trial was conducted using new viral vector technology7

  • 2 patients with severe combined immunodeficiency (SCID) received treatment using novel gamma retrovirus vector technology. The results were mixed, 1 modest response and 1 limited response

National Institutes of Health (NIH)

1996

The first engineered nuclease technology (zinc finger nuclease) was studied, this laid the groundwork for exploring the use of zinc finger nucleases for gene editing as a potential for gene therapy8

John Hopkins University

1996

 

The first generation of lentiviral vectors (LVVs) was created using 3 different plasmids (A DNA structure that can replicate without a chromosome) containing a large deactivated portion of the HIV genome, making it unlikely for HIV to replicate in human cells9

  • Second and third generation LVVs followed a couple years later containing further reduction of the original HIV genome (less than two-thirds)

Salk Institute

1999

The FDA and NIH created new programs—the Gene Therapy Clinical Trial Monitoring Plan and the Gene Transfer Safety Symposia—in an effort to ensure the safety and transparency of gene therapy clinical trials following the death of an 18-year-old patient during a clinical trial using an adenovirus vector. Additional patient protection caused delays in research at the time, but has led to greater emphasis on safety and data sharing in gene therapy research efforts since10

  • Jesse Gelsinger, an 18-year-old boy with a relatively mild form of ornithine transcarbamylase (OTC) deficiency, died while participating in an adenoviral gene therapy trial due a severe immune reaction to the vector. Investigators later found that several other patients had experienced serious side effects after being injected, but Jesse was never informed of them. This caused the FDA and NIH to enhance patient protection through 2 new programs, the Gene Therapy Clinical Trial Monitoring Plan and the Gene Transfer Safety Symposia.

University of Pennsylvania

  • Food and Drug Administration (FDA)
  • National Institutes of Health (NIH)

2000

A clinical trial of gene therapy using a gamma retrovirus raised concern about the safety of gene insertion11,12

  • Ten patients with X-linked severe combined immunodeficiency (SCID) were treated with gene therapy. While 9 out of 10 were treated, 4 of the 9 patients developed leukemia. This study demonstrated the need for improved viral vectors in gene therapy11,12

Necker Hospital for Sick Children

2002

The FDA approved the first clinical trial (in humans) using an LVV to test the safety and tolerability of a single infusion in patients with HIV. The phase 1 trial was successfully completed, opening the door for more lentiviral vector research including a phase 2 trial13

University of Pennsylvania

2003

China Food and Drug Administration approved the world’s first commercially available gene therapy to treat squamous cell carcinoma, a form of skin cancer14,15

China

2009

In a clinical trial, a genetic eye disease was treated using anadeno-associated virus (AAV)vector. Eight years later, this pivotal trial led to the FDA approval of the first gene therapy in the United States16,17

University of Pennsylvania

2010

The first engineeredTAL-effector nucleaseswere described with the ability to cause targeted mutagenesis18

University of Minnesota and Iowa State University

2010

Aself-inactivating lentiviral vectorwas first used in clinical trials of gene addition therapy in hemoglobinopathies19

University Paris Descartes

2012

 

The European Medicines Agency (EMA) approved the first adeno-associated virus (AAV)-based gene addition therapy for the treatment of lipoprotein lipase deficiency (LPLD)20

Europe

2012

Scientists developed a gene-editing technique called CRISPR/Cas9 that can modify specific DNA sequences21

UC Berkeley

2016

 

The EMA approved the first gamma retrovirus-based gene addition therapy to treat adenosine deaminase severe combined immunodeficiency

(ADA-SCID). This therapy contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence 22,23

 

Europe

2017

 

 

The FDA approved the first in vivo gene addition therapy to treat patients with a rare form of inherited blindness called biallelic RPE65 mutation-associated retinal dystrophy17

United States

2018

The first clinical trial usingCRISPR/Cas9was initiated. This study is investigating the use of CRISPR/Cas9 for gene disruption in beta hemoglobinopothies24

Stanford University,

Columbia University,

The Children’s Hospital at TriStar Centennial Medical Center, and more

  • The structure of DNA (deoxyribonucleic acid)the substance (or molecule) that carries genetic information in a human cell

    See glossary for more terms >
     was characterized by a double helix3

    James Watson, Francis Crick, Maurice Wilkins, and Rosalind Franklin

    King’s College London

  • The genetic code was discovered by deciphering the three bases of DNA in 1 of the 20 amino acids. The 19 remaining amino acids were deciphered soon after, paving the way for new technologies4

    Marshall Nirenberg, Har Khorana, and Severo Ochoa

    National Institutes of Health (NIH)

  • Researchers discovered a genetic engineering technique that allows Genetic materialrefers to materials that play a fundamental role in determining the structure and nature of a cell; these include the nucleus, mitochondria, and cytoplasm

    See glossary for more terms >
     from 1 organism to be artificially introduced, replicated, and expressed in another5

    • DNA was spliced into a plasmid carrier (a DNA structure that can replicate without a chromosome), which then inserted genetic material into an E. coli bacterium. When the bacterium reproduced, it replicated the foreign DNA and maintained the genetic material from the original organism

    Stanley N. Cohen and Herbert W. Boyer

    US-Japan joint meeting on plasmids, Hawaii

  • One of the first times gene therapy was tested in people was done without permission from the university who provided funding or the (US) National Institutes of Healtha federal agency in the US that conducts biomedical research in its own laboratories; supports the research of non-federal scientists in universities, medical schools, hospitals, and research institutions throughout the country and abroad; helps in the training of research investigators; and fosters communication of medical information

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    . The researcher lost multiple grants and NIH warned others that human experimentation would not be tolerated6

    • Martin Cline attempted gene therapy abroad without permission in 2 patients with beta-thalassemia, a rare inherited blood disorder, by transferring the beta-globin gene into their cells. This did not work because the cells did not replicate 

    Martin Cline

    The University of California, Los Angeles

  • The first gene therapy clinical trial was conducted using new Viral vectora way to deliver genetic material to a cell using the blueprint of a virus as a guide; it may be used to carry genes and change mutated cells to healthy ones

    See glossary for more terms >
    technology7

    • 2 patients with severe combined immunodeficiency (SCID) received treatment using novel gamma retrovirusa virus that uses RNA as its genetic material; when a retrovirus infects a host cell, the RNA converts into DNA, which then incorporates into the genome of the host cell

      See glossary for more terms >
      vector technology. The results were mixed, 1 modest response and 1 limited response

    Michael Blaese and French Anderson

    National Institutes of Health (NIH)

  • The first engineered Nucleasean enzyme that divides nucleic acid into nucleotides and other products

    See glossary for more terms >
     technology
    (Zinc finger nucleaseartificial restriction enzymes generated by fusing a zinc finger DNA-binding domain to a DNA-cleavage domain; ZFNs are using gene editing applications

    See glossary for more terms >
    ) was studied, this laid the groundwork for exploring the use of zinc finger nucleases for gene editing as a potential for gene therapy8

    Yang-Gyum Kim, Jooyuen Cha, and Srinivasan Chandrasegaran

    Johns Hopkins University

  • The first generation of Lentiviral vectora way to deliver genetic material to a cell using the blueprint of a lentivirus as a guide

    See glossary for more terms >
     was created using 3 different plasmids (A DNA structure that can replicate without a chromosome) containing a large deactivated portion of the HIV genome, making it unlikely for HIV to replicate in human cells9

    • Second and third generation LVVs followed a couple years later containing further reduction of the original HIV genome (less than two-thirds)

    Didier Trono and Luigi Naldini

    Salk Institute

  • The FDA and NIH created new programs—the Gene Therapy Clinical Trial Monitoring Plan and the Gene Transfer Safety Symposia—in an effort to ensure the safety and transparency of gene therapy clinical trials following the death of an 18-year-old patient during a clinical trial using an adenovirus vector. Additional patient protection caused delays in research at the time, but has led to greater emphasis on safety and data sharing in gene therapy research efforts since10 

    • Jesse Gelsinger, an 18-year-old boy with a relatively mild form of ornithine transcarbamylase (OTC) deficiency, died while participating in an adenoviral gene therapy trial due to a severe immune reaction to the vector. Investigators later found that several other patients had experienced serious side effects after being injected, but Jesse was never informed of them. This caused the FDA and NIH to enhance patient protection through 2 new programs, the Gene Therapy Clinical Trial Monitoring Plan and the Gene Transfer Safety Symposia.

    N/A

    University of Pennsylvania

    • Food and Drug Administration (FDA)
    • National Institutes of Health (NIH)
  • A clinical trial of gene therapy using a gammaretrovirus raised concern about the safety of gene insertion11,12

    • Ten patients with X-linked severe combined immunodeficiency (SCID) were treated with gene therapy. While 9 out of 10 were treated, 4 of the 9 patients developed leukemia. This study demonstrated the need for improved viral vectors in gene therapy11,12 

    Alain Fisher and Marina Cavazzana-Calvo

    Necker Hospital for Sick Children

  • The FDA approved the first clinical trial (in humans) using an LVV to test the safety and tolerability of a single infusion in patients with HIV. The phase 1 trial was successfully completed, opening the door for more lentiviral vector research including a phase 2 trial13 

    Rob Roy MacGregor

    University of Pennsylvania

  • China Food and Drug Administration approved the world’s first commercially available gene therapy to treat squamous cell carcinoma, a form of skin cancer14,15

    China Food and Drug Administration

    China

  • In a clinical trial, a genetic eye disease was treated using an adeno-associated virus Adeno-associated virusa single-stranded DNA virus that depend on adenoviruses for replication

    See glossary for more terms >
     vector. Eight years later, this pivotal trial led to the FDA approval of the first gene therapy in the United States16, 17

    Jean Bennett

    University of Pennsylvania

  • The first engineered Transcription activator-like effector-based nucleases (TALEN)an array of single-protein modules, or nuclease, where each module recognizes a single DNA base pair. These nucleases are derived from transcription activator-like effectors, which means they are derived from plant bacteria

    See glossary for more terms >
     were described with the ability to cause targeted mutagenesis18

    Michelle Christian, Tomas Cermak, and Erin L. Doyle

    University of Minnesota and Iowa State University

  • A Self-inactivating lentiviral vectora vector that, through a process of deleting and manipulating lentiviral components, is no longer able to replicate

    See glossary for more terms >
     was first used in clinical trials of Gene additionadds functioning genetic material to do the work of a faulty gene

    See glossary for more terms >
     therapy in hemoglobinopathies19

    Philippe Leboulch

    University Paris Descartes

  • The European Medicines Association (EMA)the regulatory agency responsible for scientific evaluation of medicine for potential use in the European Union

    See glossary for more terms >
    approved the first adeno-associated virus (AAV)-based gene addition therapy for the treatment of lipoprotein lipase deficiency (LPLD)20

    European Medicines Agency (EMA)

    Europe

  • Scientists developed a gene-editing technique called Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9a laboratory tool that uses a specially designed RNA molecule to guide a Cas9 enzyme to a specific sequence of DNA so it can change or edit pieces of it

    See glossary for more terms >
     that can modify specific DNA sequences21

    Jennifer Duodna, Emmanuelle Charpentier and team

    UC Berkeley

  • The EMA approved the first gamma retrovirus-based gene addition therapy to treat adenosine deaminase severe combined immunodeficiency (ADA-SCID). This therapy contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence22, 23

    European Medicines Agency (EMA)

    Europe

  • The FDA approved the first In vivoinside the body

    See glossary for more terms >
     gene addition therapy to treat patients with a rare form of inherited blindness called biallelic RPE65 mutation-associated retinal dystrophy17

    US Food and Drug Administration (FDA)

    United States

  • The first clinical trial using Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9a laboratory tool that uses a specially designed RNA molecule to guide a Cas9 enzyme to a specific sequence of DNA so it can change or edit pieces of it

    See glossary for more terms >
     was initiated. This study is investigating the use of CRISPR/Cas9 for gene disruption in beta hemoglobinopothies24

    N/A (investigators not listed)

    Stanford University, Columbia University, The Children’s Hospital at TriStar Centennial Medical Center, and more

History of Gene Therapy
Explore the evolution of gene therapy over time by taking a closer look at several key milestones
History of Gene Therapy
Explore the evolution of gene therapy over time by taking a closer look at several key milestones

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References

1. Wirth T, Parker N, Ylä-Hertuala. History of gene therapy. Gene. 2013;252(2):62-169. 2. Food and Drug Administration. FDA continues strong support of innovation in development of gene therapy products. Press release. Accessed March 4, 2020. https://www.fda.gov/news-events/pressannouncements/fda-continues-strong-support-innovation-development-gene-therapyproducts 3. Science History Institute. James Watson, Francis Crick, Maurice Wilkins, and Rosalind Franklin. Accessed March 4, 2020. https://www.sciencehistory.org/historical-profile/james-watson-francis-crickmaurice-wilkins-and-rosalind-franklin 4. Nirenberg M. Historical review: Deciphering the genetic code—a personal account. Trends Biochem Sci. 2004;29(1):46-54. 5. Science History Institute. Herbert W Boyer and Stanley N Cohen. Accessed March 4, 2020. https://www.sciencehistory.org/historical-profile/herbert-w-boyer-and-stanley-n-cohen 6. Sun M. Cline loses two NIH grants. Science. 1981;214(4525):1220. 7. Blaese RM, Culver KW, Miller D, et al. T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science. 1995;270(5235):475-480. 8. Kim YG, Cha J, Chandrasegaran S. Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain. Proc Natl Acad Sci U S A. 1996;93(3):1156-1160. 9. Naldini L, Blomer U, Gallay P, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science. 1996;272(5259):263-267. 10. Sibbald B. Death but one unintended consequence of gene-therapy trial. CMAJ. 2001;164(11):1612. 11. The Journal of Clinical Investigation. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. Accessed April 12, 2020. https://doi.org/10.1172/JCI35700. 12. The Journal of Clinical Investigation. Gene therapy for severe combined immunodeficiency: are we there yet? Accessed April 12, 2020. https://doi.org/10.1172/JCI30953. 13. Humeau L. From the bench to the clinic: story and lessons from VRX496, the first lentivector ever tested in a phase 1 clinical trial. Presented at: Beilstein Bozen Symposium; May 15-May 19, 2006; Bozen, Italy. 14. Pearson S, Jia H, Kandachi K. China approves first gene therapy. Nat Biotechnol. 2004;22(1):3-4. 15. Daley J. Gene therapy arrives. Nature. 2019;576:S12-S13. 16. Maguire AM, High KA, Auricchio A, et al. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet. 2009;374(9701):1597‐1605. 17. Luxturna (voretigene neparvovec-ryzl) [prescribing information]. Philadelphia, PA: Spark Therapeutics, Inc.; 2017. 18. Christian M, Cermak T, Doyle EL, et al. Targeting DNA double-strand breaks with TAL effector nucleases. Genetics. 2010;186(2):757‐761. 19. Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature. 2010;467(7313):318‐322. 20. Glybera® (alipogene tiparvovec) [Summary of Product Characteristics]. Amsterdam, Netherlands: uniQure; 2012. 21. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E.  A programmable dual RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337(6096);816-821. 22. Aiuti A, Roncarolo MG, Naldini L. Gene therapy for ADA-SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products. EMBO Mol Med. 2017;9(6):737-740. 23. Strimvelis Summary of Product Characteristics, GlaxoSmithKline (GSK); 2016. 24. Cross R. CRISPR is coming to the clinic this year. Chem Eng News. 2018;96(2):18-19. 

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