Gene therapy is a type of treatment designed to modify the expression of an individual’s genes or to correct abnormal genes to treat a disease.
R. Michael Blaese, W. French Anderson and Kenneth Culver at a press conference announcing the start of the first gene therapy trial for treating children with severe combined immunodeficiency, 13 September 1990. Source: National Cancer Institute
Connections Cancer immunotherapy
In the early days gene therapy was seen as highly attractive, in part because it was presumed that such treatment could be developed relatively quickly, moving swiftly from proof of concept into clinical trials. Commercial investment in the area, however, dramatically plunged in the late 1990s following the death of the first patient in a gene therapy trial. Interest in gene therapy only began to pick up again after 2008 which saw saw the creation of dozens of new start-ups around gene therapy. These were founded on the back of sponsorship from pharmaceutical companies and the stock market. Just how much importance is now attached to gene therapy can be seen by the stock market’s valuation of Juno Therapeutics. In 2014, just one year after Juno was set up, the company was valued at US$4 billion.
Scientists first began to demonstrate that it was possible to incorporate new genetic functions in mammalian cells in the late 1960s. Several methods were used to achieve this. One involved injecting genes with a micropipette directly into a living mammalian cell. Another way was to expose cells to a precipitate of DNA containing the desired genes. Alternatively a virus could be used as a vehicle, or vector, to deliver the genes into cells.
One of the first people to report the direct incorporation of functional DNA into a mammalian cell was Lorraine Kraus at the University of Tennessee. In 1961 she successfully managed to genetically alter the haemoglobin of cells from bone marrow taken from a patient with sickle-cell anaemia. She did this by incubating the patient’s cells in tissue culture with DNA extracted from a donor with normal haemoglobin. In 1968, Theodore Friedmann, Jay Seegmiller and John Subak-Sharpe at the National Institutes of Health, Bethesda, succeeded in correcting genetic defects associated with Lesch-Nyhan syndrome, a debilitating neurological disease. They did this by adding foreign DNA to cultured cells collected from patients suffering from the disease.
Humans were first tested with gene therapy in 1970. The trial was carried out by Stanfield Rogers, an American physician, together with H. G. Terheggen, a German paediatrician. Their trial was directed towards treating two very young West German sisters suffering from hyperargininemia, an extremely rare genetic disorder that prevents the production of arginase. This is an enzyme that helps prevent the build up of arginine in bodily fluids. Any accumulation can cause brain damage, epilepsy and other neurological and muscular problems. Each child was injected with a type of rabbit virus (Shope papilloma) known to induce the production of arginase. The treatment represented the last desperate measure to rescue the children.
Rogers was inspired to treat the sisters as a result of his discovery of abnormal levels of arginine in the blood of laboratory technicians at Oak Ridge National Laboratory who worked with the virus. None of the technicians experienced ill-effects from the virus. One of them was showing low levels of arginine 20 years after her last exposure to the virus. Rogers connected the technicians’ abnormal arginine levels with the viral gene encouraging the production of arginase. As early as 1966, Rogers suggested that viruses could provide a vehicle for delivering functional genes. He hoped that in giving the virus to the girls he could transfer genetic instructions to the children’s cells to produce the arginase enzyme. Following treatment a third sister was born afflicted with hyperargininemia. She was again injected with the same virus. Sadly none of the sisters responded to the treatment.
Efforts to develop gene therapy did not stop with the German sisters. A new chapter for such treatment opened with the the arrival of recombinant DNA in the early 1970s. The technique provided two key tools. Firstly, a means to clone specific disease genes. Secondly, an efficient method for gene transfer. Some of the first scientists to grasp the potential of the technology for gene therapy were Theodore Friedmann and Richard Roblin. In 1972 they published an article in Science suggesting genetically modified tumour viruses could potentially carry the necessary genetic information needed to treat genetic disorders.
The first gene therapy that was tried out in humans after Friedmann and Roblin's article was for beta-thalassemia, an inherited blood disorder that usually results in premature death. It is linked to a defect in a gene for beta-globin. This gene was first cloned in 1976 by scientists at Cold Spring Harbor Laboratory and Harvard University. It was the first ever disease gene cloned. Three years later, a team led by Martin Cline at the University of California, Los Angeles, reported the successful introduction of the gene into the bone marrow of irradiated mice.
Thereafter Cline and his team attempted to treat two beta-thalassemia patients, one in Italy and another in Israel. This they did by inserting the beta-globin gene into bone marrow extracted from the patients and then reinfusing the cells back into them. Disappointingly neither of the patients benefited from the treatment. Added to this, Cline was immediately criticised for having carried out the trial without having secured the necessary permission from his home institution’s Institutional Review Board. His reputation was further eroded by the fact that he had lacked sufficient animal data to demonstrate the effectiveness of the procedure. The storm that followed not only lost Cline his university chair and most of his National Institutes of Health (NIH) funding, but also sparked a major public debate about how far gene therapy was ethically and socially acceptable. In the aftermath tighter regulations were installed for the future testing of gene therapy in humans. These were to be overseen by the NIH’s Recombinant DNA Advisory Committee (RAC).
The 1980s saw the beginning of a new era in gene therapy fueled by the discovery of retroviruses. Such viruses had the advantage that their genome was very simple and they possessed an enzyme called reverse transcriptase. This made them a very efficient tool for gene transfer. A key pioneer in the field was Richard Mulligan, a researcher at Massachusetts Institute of Technology who had completed his doctorate under Paul Berg, an important figure in the development of recombinant DNA at Stanford University. Mulligan spearheaded the development of the first suitable retroviral vector for gene therapy. In 1983 Mulligan and colleagues managed to genetically modify a mouse leukemia retrovirus so that it was incapable of reproduction in humans and could deliver any desired DNA. The vector also contained a selective marker, a piece of DNA from Escherichia coli bacteria, which made it possible to identify how many genes a cell picked up during gene transfer.
By 1989 French Anderson, a geneticist at the NIH’s National Heart, Lung and Blood Institute, had secured the necessary permission from the RAC to begin the first approved clinical trial with gene therapy. He was to carry this out with the help of Michael Blease, a paediatrician and immunologist. Their aim was to try out a gene therapy to treat children with severe combined immunodeficiency, an inherited immune disorder caused by a defective adenosine deaminase gene. Most children born with the disorder did not live long and only survived by being confined in sterile plastic enclosures, giving rise to the term ‘bubble disease’. Those suffering from the condition had only two treatment options. The first was to have a bone marrow transplant, but this was hampered by the need to find a matching donor. The second was to have frequent injections of PEG-ADA, a synthetic form of the ADA enzyme. While children who had such treatment usually showed a marked improvement after the first injection, this was of short duration and subsequent doses were largely ineffective.
Before starting to treat children Anderson’s team partnered with Steven Rosenberg at the National Cancer Institute (NCI) to test out the safety of their proposed procedure. The purpose of the experiment, conducted in May 1989, was not only to test out the safety of the retroviral vector, but also to establish how much of a marked gene it could transfer and how long the gene lasted. The experiment necessitated first cultivating tumour infiltrating lymphocytes (TIL cells), a type of tumour-killing cell. This involved the incubation of white blood cells removed from the tumour of a 52 year old man dying from malignant melanoma with interleukin-2, a molecule found to activate T in the destruction of cancer cells in the 1960s. Once produced the TIL cells had a DNA marker inserted and were then reinfused into the patient. Over the course of the next eleven months the same procedure was repeated in seven more terminal patients at the NCI with malignant melanoma. Encouragingly those given the treatment were observed to absorb the marker genes with no ill-effects. In addition, the procedure appeared to help a third of all the patients. One experienced a near-complete remission. The study marked a major turning point. Firstly, it established the feasibility and safety of gene therapy. Secondly, it opened the path to the development of gene therapy for cancer.
Anderson’s team was ready to start trying out the gene therapy in children with ADA-SCID in early 1990. The first patient tested was Ashanti DeSilva, a four year old girl. Her treatment lasted twelve days. Over this period Ashanti had her blood cells extracted and a new working copy of the ADA gene was inserted into them before they were reinfused into her. In many ways the procedure mimicked a bone marrow transplant (BMT). The goal was to replenish Ashanti’s blood cells with ones that could produce ADA. One of the advantages with the gene therapy was there was no risk of rejection because the cells originated from Ashanti. To everyone’s delight the treatment proved highly effective. Ashanti improved so much she no longer needed to be kept in isolation and was able to start school. She remains alive to this day.
Numerous gene therapy trials were launched in the 1990s in the wake of the success with Ashanti. A significant shift took place during this decade. Critically the field moved away from just looking to treat rare diseases caused by a single gene, as had been the case with Ashanti. By 2000 gene therapy had been tried out in nearly 3,000 patients in almost 400 trials. The bulk of these trials were directed towards cancer. Other conditions were also investigated, including cardiovascular disease, AIDS, cystic fibrosis and Gaucher disease.
By the end of the 1990s, however, some of the early enthusiasm for gene therapy witnessed at the beginning of the decade had begun to wane. This was because researchers were struggling to get the therapy to work. They were greatly hampered by the inefficiency of the retroviral vectors they had to hand. Negative attitudes to gene therapy rapidly sharpened following the report of the first death in a gene therapy trial in September 1999. The person who died was Jesse Gelsinger, an 18 year old American. He had been a volunteer in a dosing escalation trial headed by James M Wilson designed to treat newborn infants with a usually fatal inherited a metabolic disorder known as ornithine transcarbamylase deficiency which leads to the buildup of excessive ammonia in the body. Jesse had suffered from the condition himself since birth, but had managed to keep it in check by restricting his diet and taking special medications. Gelsinger was in the last cohort to be given the treatment - the one given the highest dose. Four days after treatment Gelsinger died from major organ failure caused by his violent immune reaction to the vector used in the treatment. The vector was derived from adenovirus, a group of viruses first isolated from the tonsils and adenoid tissue of children in the early 1950s. Such viruses had the advantage that they were already well characterised and had only a small genome so were easy to manipulate. It was considered relatively harmless because most people carry adenoviruses without experiencing any significant clinical symptoms.
Investigations into Jesse’s death revealed insufficient care had been taken during the trial and poor clarity in its safety guidelines. Jesse’s tragedy led to the enforcement of greater regulations for gene therapy trials. However, he was not the last to suffer the consequences of an adenoviral vector. Three years later, in 2002, a number of British and French children were found to have developed T cell leukaemia three years after receiving gene therapy for a form of SCID linked to a defect on the X chromosome. This turned out to have been caused by an adenoviral vector that unexpectedly integrated into a part of the genome that activated a gene for leukaemia. Most adenoviruses were unable to integrate into the host genome.
Despite the difficulties, gene therapy began to turn a corner in the following decade. This was aided by the arrival of a new generation of safer and more effective vectors. During this time positive results began to surface from a number of gene therapy trials. Most of these studies were small-scale academic studies.
In 2007 a small trial was conducted by Jean Bennett, an ophthalmologist at the University of Pennsylvania which demonstrated gene therapy could provide a promising treatment for inherited retinal disease. Subsequent trials in more patients carried out in 2015 backed up this evidence. In addition to eye disease, gene therapy was found to help haemophilia patients, a number of whom were able to abandon taking blood clotting factor treatment. Good news also emerged in 2015 from trials directed towards the use of gene therapy for rarer single-mutation blood diseases like thalassemia and sickle-cell anaemia, with some patients able to stay healthy without blood transfusions. In 2016 a small trial indicated that gene therapy could help in the treatment of cerebral adrenoleukodystrophy, an inherited disorder that affects the central nervous system. The same year another small trial showed it could help in the treatment of spinal muscular atrophy, a neuromuscular disease that is one of the leading causes of genetic death in infants.
The first gene therapy was licensed in China in 2003. Designed for the treatment of head and neck cancer, this treatment did not make it across to other countries. It would take another nine years before the first gene therapy was approved in Europe. This was developed by UniQure, a Dutch company, for treating a rare disease that inflames the pancreas. By 2016 Europe had licensed a second gene therapy, one developed by GlaxoSmithKline for children suffering from ADA-SCID. In 2017 the US approved its first gene therapy. This was for treating acute lymphoblastic leukaemia. Developed by Novartis, the foundations for the treatment were laid by the preliminary trial Anderson and Rosenberg ran to establish the safety of gene therapy for treating children with ADA-SCID in 1989.
Gene therapy can involve the insertion of a copy of a new gene, modifying or inactivating a gene, or correcting a gene mutation. Such changes are made with the help of a vector derived from a genetically modified virus. Several different viral vectors are now available for this purpose. This includes adenoviral vectors which are now used in most gene therapies undergoing clinical trial. Such vectors work best in cells that do not divide, such as those in the brain or retina.
Another popular vector are derived from lentiviruses, a retroviral group of viruses. This includes the human immunodeficiency virus and the herpes simplex virus. Lentiviral vectors emerged in the late 1990s out of efforts to understand and cure AIDS. Such vectors are attractive because they can carry large quantities of genes and work in non-dividing cells. It is difficult, however, to predict where they will integrate into the genome which poses safety issues. For this reason, lentiviral vectors are mostly used in gene therapies that genetically modify cells extracted from patients. Where lentiviral vectors are proving particularly helpful is in the introduction of genes into the genomes of cells that are generally difficult to modify. Lentiviral vectors made from the herpes simplex virus are currently being explored as a means to develop gene therapies for pain and brain diseases.
Gene therapy is now on the cusp of a new horizon as a result of the development of CRISPR-Cas9. One of the advantage of the new technology is that it allows for much more precise genetic changes than before. Towards the end of 2016 a group of Chinese scientists led by the oncologist Lu You at Sichuan University started a safety trial to see if it was possible to treat cancer patients by using CRISPR-Cas to disable a particular gene in their cells that codes for the PD1 protein which often impedes a cell’s immune response to cancer. A few months later, in early 2017, an American team headed by Carl June at the University of Pennsylvania initiated another similar trial.
While gene therapy has made remarkable progress in the last few years, its development still raises significant questions in terms of safety. One of the major differences between gene therapy and conventional small molecule drugs or other biological products, like protein therapeutics, is that once gene therapy is administered it is difficult to stop treatment. It is still too early to know how long the effects of a gene therapy can last. Moreover, too few patients have been given gene therapy for any length of time to know whether it poses any safety risks long term.
Another major stumbling block is the fact that the price of gene therapy has so far been incredibly high. They are currently some of the most expensive treatments on the market. This in part reflects the fact that most gene therapies need to be custom-made to individual patients.
This piece was written by Lara Marks. It draws on the work of Courtney Addison and her chapter ‘Gene therapy: An evolving story’, in Lara V Marks, ed, Engineering Health: How biotechnology changed medicine, (Royal Society of Chemistry, September 2017).
Gene therapy: timeline of key events
|16 Dec 1961||First successful direct incorporation of functional DNA in human cell||Kraus||University of Tennessee|
|10 Dec 1966||First evidence published suggesting a virus could provide delivery tool for transferring functional genes||Rogers||Oak Ridge National Laboratory|
|19 Oct 1968||American scientists demonstrate that adding foreign genes to cultured cells from patients with Lesch-Nethan syndrome can correct genetic defects that cause the neurological disease||Friedmann, Seegmiller||National Institutes of Health|
|1970 - 1975||Three West German very young sisters fail to respond to first ever administered gene therapy||Rogers, Terheggen||Oak Ridge National Laboratory, Cologne municipal hospital|
|3 Mar 1972||First time gene therapy proposed as treatment for genetic disorders||Friedmann, Roblin||Salk Institute|
|June 1976||First human disease gene, beta-globin, cloned||Maniatis, GekKee, Efstratiadis, Kafatos|
|1979||Beta-thalassemia gene successfully inserted into bone marrow of irradiated mice||Cline||University of California Los Angeles|
|1980||Gene therapy unsuccessfully tried out in two patients with beta-thalaessemia sparks controversy||Cline||University of California Los Angeles|
|22 Apr 1982||First experiment launched to test feasibility of inserting a corrective DNA in the right place in the human genome||Smithies||University of Wisconsin|
|May 1983||Creation of first retroviral vector suitable for gene therapy||Mann, Mulligan, Baltimore||Massachusetts Institute of Technology, Whitehead Institute for Biomedical Research|
|1984||Experiment published demonstrating possibility of inserting a corrective DNA in the right place in genome of mammalian cells||Smithies, Koralewski, Song, Kucherlapati||University of Wisconsin|
|January 1985||NIH publishes its first draft guidelines for proposing experiments in human somatic cell gene theray|
|19 Sep 1985||Technique published for the accurate insertion of a corrective DNA in the human genome||Smithies, Gregg, Boggs, Koralewski, Kucherlapati||University of Wisconsin|
|May 1989||First human test demonstrated safety of retroviral vector for gene therapy and potential of laboratory produced tumor killing cells for cancer immunotherapy||Anderson, Rosenberg||National Institutes of Health|
|December 1989||First use of genetically engineered T cells to redirect T cells to recognise and attack tumour cells||Gross, Waks, Eshhar||Weizmann Institute|
|December 1989||Concept of enhancing T cells using chimeric antigen receptors published for first time||Gross, Waks, Eshhar||Weizmann Institute|
|January 1990||Gene therapy concept proven in first human trials||Kasid, Morecki, Aebersold, Cornetta, Culver, Freeman, Director, Lotze, Blaese, Anderson||National Cancer Institute|
|30 Aug 1990||Treatment with gene modified tumour-infiltrating lymphocytes shown to be promising immunotherapy for patients with advance melanoma||Rosenberg, Aebersold, Cornetta, Kasid, Morgan, Moen, Karson, Lotze, Yang, Topalian, Merino, Culver, Miller, Blaese, Anderson||National Cancer Institute|
|September 1990||Four year old Ashanti DeSilva becomes first patient successfully treated with gene therapy for severe combined immunodeficiency caused by defective ADA gene||Anderson, Blease, DeSilva||National Institutes of Health|
|1992||Stem cells used as vectors to deliver the genes needed to correct the genetic disorder SCID||Bordignon||Vita-Salute San Raffaele University|
|15 Jan 1993||Chimeric receptor genes added to T lymphocytes shown to enhance power of adoptive cellular therapy against tumours||Eshhar, Waks, Gross, Schindler||Weizmann Institute|
|October 1993||FDA lays out regulations governing gene therapy|
|September 1999||Death of the first patient in a gene therapy trial prompts major setback for the field||Gelsinger, Wilson||University of Pennsylvania|
|1999 - 2002||Multi-centre trials with gene therapy using stem cells to treat children with SCID||Bordignon|
|2000||Two French boys suffering from SCID reported to be cured using gene therapy|
|1 Jan 2002||Suspension of French and US gene therapy trials for treating SCID children|
|1 Jan 2003||First human trial of gene therapy using modified lentivirus as a vector|
|October 2003||China approved the world's first commercial gene therapy to deliver the p53 gene, via an adenovirus vector, to treat squamous cell head and neck cancer|
|3 Apr 2005||Zinc finger method reported capable of modifying some genes in the human genome, laying the foundation for its use as tool to correct genes for monogenic disorders||Urnov, Miller, Lee, Beausejour||Sangamo BioSciences, University of Texas Southwester Medical Center|
|6 Oct 2006||Genetically engineered lymphocytes shown to be promising cancer treatment||Morgan, Dudley, Wunderlich, Hughes, Yang, Sherry, Royal, Topalian, Kammula, Restifo, Zheng, Nahvi Vries, Rogers-Freezer, Mavroukakis, Rosenberg||National Cancer Institute|
|15 Oct 2006||Adoptive cellular therapy using chimeric antigen receptor T cells shown to be safe in small group of patients with ovarian cancer||Kershaw, Westwood, Parker, Wang, Eshhar, Mavroukakis, White, Wunderlich, Canevari, Rogers-Freezer, Chen, Yang, Rosenberg, Hwu||National Cancer Institute, University of Melbourne, M.D. Anderson Cancer Center, Weizmann Institute, Istituto Nazionale Tumori|
|2007||Small trial published demonstrating possibility of using gene therapy for inherited retinal disease||Bennett||University of Pennsylvania|
|1 May 2008||Zinc finger method explored as means to develop treatment for glioblastoma (brain tumour)||Reik, Zhou, Wagner, Hamlett||Sangamo BioSciences|
|29 Jun 2008||Zinc finger method used to make HIV-resistant CD4 cells to develop immunotherapy for HIV||Perez, Wang, Miller, Jouvenot||Abramson Family Cancer Research Institute, Children's Hospital of Philadelphia, Sangamo BioSciences, Bayer|
|2009||Almost blind child with rare inherited eye disease gains normal vision following gene therapy|
|2009||Gene therapy halts progression of degenerative disease adrenoleukodystrophy in two boys|
|January 2010||Gene therapy for treatment of lipoprotein lipase deficiency fails to win European approval||Amsterdam Molecular Therapeutics, UniQure|
|January 2010||Gene therapy successful in treating beta-thalassaemia|
|2010 - 2013||Studies show CD19-specific CAR-modified T cells to be promising treatment in patients with B cell malignancies||Kochenderfer, Kalos, Brentjens||National Cancer Institute, National Institutes of Health, Memorial Sloan-Kettering Cancer Center, University of Pennsylvania|
|1 Jan 2011||Gene therapy reduces symptoms in six patients with haemophilia B|
|10 Mar 2011||Patient suffering from acute myeloid leukaemia is cured of HIV-1 after receiving bone marrow stem cells transplanted from donor with mutated CCR5 gene. This awakens interest in developing HIV treatment that renders a patient's cells resistant to HIV-1||Allers, Hutter, Hofmann, Loddenkemper, Rieger||Charite-University Medicine Berlin|
|14 Jul 2011||Gene repair kit used successfully to treat blood-clotting disorder haemophilia in mice||Li, Haurigot, Doyon, High||Children's Hospital Philadelphia, Sangamo Biosciences, University of Philadelphia|
|January 2012||European Union asks European Medicines Agency to reconsider approval of alipogene tiparvovec||Amsterdam Molecular Therapeutics, UniCure|
|July 2012||First gene therapy approved for treatment of patients with familial lipoprotein lipase deficiency||Amsterdam Molecular Therapeutics|
|1 Jun 2013||Basic studies conducted with TALENs to see if can correct mutant genes associated with Epidermolysis Bullosa, a rare inherited skin disorder||Osborn, Starker, Colby, McElroy||University of Minnesota, National Centre for Tumor Diseases Heidelberg, German Cancer Research Centre, Harvard University|
|October 2013||Fiven children with ADA-SCID successfully treated with gene therapy|
|January 2014||Eyesight reported to improve in six patients suffering from choroideremia after receiving gene therapy||MacLaren||Oxford University|
|March 2014||Promising results announced from trial conducted with HIV patients|
|6 Mar 2014||Phase I trial using Zinc finger nuclease modified CD4 cells to treat 12 HIV patients shows the approch is safe.||Tebas, Stein, Tang, Frank||University of Pennsylvania|
|10 Sep 2014||Mice trials show CD4 T-cells genetically modified with Zinc fingers could be effective HIV-1 gene therapy||Yi, Choi, Bharaj, Abraham||Texas Tech University, University of North Carolina|
|1 Jan 2015||US FDA cleared Investigative Drug Application for clinical trial of gene therapy for haemophila B. The therapy was the first in vivo genome editing application to enter the clinic||Ewing, Zaia||Sangamo Biosciences, City of Hope National Medical Center|
|5 Nov 2015||First report of successful use of gene therapy to treat leukaemia||Vehs, Quasim||Great Ormond Street|
|11 Dec 2015||Preliminary results presented for phase 2 trial using Zinc finger nuclease modified CD4 and CD8 cells to treat HIV patients||Sangamo Biosciences|
|31 Dec 2015||CRISPR successfully used to improve muscle function in mouse model of Duchenne muscular dystrophy, opening way to use CRISPR to correct genetic mutatiuons in affected tissues of sick patients||Nelson, Gersbach, Hakim, Ousterout, Thakore||Duke University, University of Missouri, University of North Carolina, Massachusetts Institute of Technology, Harvard University|
|6 Feb 2017||Gene therapy shown to restore hearing in deaf mice||Landegger, Pan, Askew, Wassmer, Gluck, Galvin, Taylor, Forge, Sankovic, Holt, Vandenberghe||Eaton Peabody Laboratories, Harvard Medical School, Medical University of Vienna, UCL, Boston's Children's Hospital, Harvard Stem Cell Institute, University of North Carolina, Grousbeck Gene Therapy Center|
|2 Mar 2017||Gene therapy reported to successfully reverse sickle cell disease in first patient||Ribell, Hacien-Bey-Abina, Payen, Magnani, Leboulch||University of Paris|
|12 Jul 2017||US FDA Oncologic Drugs Advisory Committee recommended the approval of the first adoptive cell therapy (CAR-T cell therapy) for B cell acute leukaemia||Novartis, University of Pennsylvania|
|30 Aug 2017||USA FDA approved CAR-T therapy for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia||Novartis, University of Pennsylvania|
|4 Oct 2017||Gene therapy shown in clinical trials to halt progression of adrenoleukodystrophy, a fatal brain disease inherited by boys||Eichler, Duncan, Williams||Harvard University, Bluebird Bio, Boston Children’s Hospital|
|16 Nov 2017||First patient receives therapy involving gene editing inside the body||Harmatz, Madeux||University of California San Francisco|
16 Dec 1961
First successful direct incorporation of functional DNA in human cell
10 Dec 1966
First evidence published suggesting a virus could provide delivery tool for transferring functional genes
19 Oct 1968
American scientists demonstrate that adding foreign genes to cultured cells from patients with Lesch-Nethan syndrome can correct genetic defects that cause the neurological disease
1970 - 1975
Three West German very young sisters fail to respond to first ever administered gene therapy
3 Mar 1972
First time gene therapy proposed as treatment for genetic disorders
First human disease gene, beta-globin, cloned
Beta-thalassemia gene successfully inserted into bone marrow of irradiated mice
Gene therapy unsuccessfully tried out in two patients with beta-thalaessemia sparks controversy
22 Apr 1982
First experiment launched to test feasibility of inserting a corrective DNA in the right place in the human genome
Creation of first retroviral vector suitable for gene therapy
Experiment published demonstrating possibility of inserting a corrective DNA in the right place in genome of mammalian cells
NIH publishes its first draft guidelines for proposing experiments in human somatic cell gene theray
19 Sep 1985
Technique published for the accurate insertion of a corrective DNA in the human genome
First human test demonstrated safety of retroviral vector for gene therapy and potential of laboratory produced tumor killing cells for cancer immunotherapy
First use of genetically engineered T cells to redirect T cells to recognise and attack tumour cells
Concept of enhancing T cells using chimeric antigen receptors published for first time
Gene therapy concept proven in first human trials
30 Aug 1990
Treatment with gene modified tumour-infiltrating lymphocytes shown to be promising immunotherapy for patients with advance melanoma
Four year old Ashanti DeSilva becomes first patient successfully treated with gene therapy for severe combined immunodeficiency caused by defective ADA gene
Stem cells used as vectors to deliver the genes needed to correct the genetic disorder SCID
15 Jan 1993
Chimeric receptor genes added to T lymphocytes shown to enhance power of adoptive cellular therapy against tumours
FDA lays out regulations governing gene therapy
Death of the first patient in a gene therapy trial prompts major setback for the field
1999 - 2002
Multi-centre trials with gene therapy using stem cells to treat children with SCID
Two French boys suffering from SCID reported to be cured using gene therapy
Suspension of French and US gene therapy trials for treating SCID children
First human trial of gene therapy using modified lentivirus as a vector
China approved the world's first commercial gene therapy to deliver the p53 gene, via an adenovirus vector, to treat squamous cell head and neck cancer
3 Apr 2005
Zinc finger method reported capable of modifying some genes in the human genome, laying the foundation for its use as tool to correct genes for monogenic disorders
6 Oct 2006
Genetically engineered lymphocytes shown to be promising cancer treatment
15 Oct 2006
Adoptive cellular therapy using chimeric antigen receptor T cells shown to be safe in small group of patients with ovarian cancer
Small trial published demonstrating possibility of using gene therapy for inherited retinal disease
1 May 2008
Zinc finger method explored as means to develop treatment for glioblastoma (brain tumour)
29 Jun 2008
Zinc finger method used to make HIV-resistant CD4 cells to develop immunotherapy for HIV
Almost blind child with rare inherited eye disease gains normal vision following gene therapy
Gene therapy halts progression of degenerative disease adrenoleukodystrophy in two boys
Gene therapy for treatment of lipoprotein lipase deficiency fails to win European approval
Gene therapy successful in treating beta-thalassaemia
2010 - 2013
Studies show CD19-specific CAR-modified T cells to be promising treatment in patients with B cell malignancies
Gene therapy reduces symptoms in six patients with haemophilia B
10 Mar 2011
Patient suffering from acute myeloid leukaemia is cured of HIV-1 after receiving bone marrow stem cells transplanted from donor with mutated CCR5 gene. This awakens interest in developing HIV treatment that renders a patient's cells resistant to HIV-1
14 Jul 2011
Gene repair kit used successfully to treat blood-clotting disorder haemophilia in mice
European Union asks European Medicines Agency to reconsider approval of alipogene tiparvovec
First gene therapy approved for treatment of patients with familial lipoprotein lipase deficiency
1 Jun 2013
Basic studies conducted with TALENs to see if can correct mutant genes associated with Epidermolysis Bullosa, a rare inherited skin disorder
Fiven children with ADA-SCID successfully treated with gene therapy
Eyesight reported to improve in six patients suffering from choroideremia after receiving gene therapy
Promising results announced from trial conducted with HIV patients
6 Mar 2014
Phase I trial using Zinc finger nuclease modified CD4 cells to treat 12 HIV patients shows the approch is safe.
10 Sep 2014
Mice trials show CD4 T-cells genetically modified with Zinc fingers could be effective HIV-1 gene therapy
1 Jan 2015
US FDA cleared Investigative Drug Application for clinical trial of gene therapy for haemophila B. The therapy was the first in vivo genome editing application to enter the clinic
5 Nov 2015
First report of successful use of gene therapy to treat leukaemia
11 Dec 2015
Preliminary results presented for phase 2 trial using Zinc finger nuclease modified CD4 and CD8 cells to treat HIV patients
31 Dec 2015
CRISPR successfully used to improve muscle function in mouse model of Duchenne muscular dystrophy, opening way to use CRISPR to correct genetic mutatiuons in affected tissues of sick patients
6 Feb 2017
Gene therapy shown to restore hearing in deaf mice
2 Mar 2017
Gene therapy reported to successfully reverse sickle cell disease in first patient
12 Jul 2017
US FDA Oncologic Drugs Advisory Committee recommended the approval of the first adoptive cell therapy (CAR-T cell therapy) for B cell acute leukaemia
30 Aug 2017
USA FDA approved CAR-T therapy for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia
4 Oct 2017
Gene therapy shown in clinical trials to halt progression of adrenoleukodystrophy, a fatal brain disease inherited by boys
16 Nov 2017
First patient receives therapy involving gene editing inside the body