Gene therapy

Definition

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

Importance

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.

Discovery

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.

Application

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.

Issues

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

Lorraine Kraus incubated bone marrow cells from a patient with sickle-cell anaemia with DNA from healthy donor. L.M. Kraus, ‘Formation of different haemoglobins in tissue culture of human bone marrow treated with human deoxyribonucleic acid’, Nature, 4807 (1961) 1055-57. 1961-12-16T00:00:00+0000S. Rogers, ‘Shope papilloma virus: A passenger in man and its significance to the potential control of the host genome’, Nature, 212, 1120 (1966), 1220-22.1966-12-10T00:00:00+0000T. Friedmann, J.E. Seegmiller, J.H. Subak-Sharpe, 'Metabolic Cooperation between Genetically Marked Human Fibroblasts in Tissue Culture', Nature, 220 (1968), 272-74.1968-10-19T00:00:00+0000Treatment given by Stanfield Rogers, Oak Ridge Laboratory and H G Terheggen, municipal hospital, Cologne, in attempt to cure hyperargininemia, an extremely rare genetic disorder that causes brain damage. H. G. Terheggen, A. Lowenthal, F. Lavinha and J.P. Colombo, Familial hyperargininaemia, Archive Disease Childhood, 50 (1975), 57.1970-01-01T00:00:00+0000T. Friedmann, R. Roblin, 'Gene therapy for human genetic disease?'. Science, 175/4025 (1972), 949-55.1972-03-03T00:00:00+0000T. Maniathis, S. GekKee, A. Efstratiadis, F.C.Kafatos, ‘Amplification and characterization of a beta\r\n-globin gene synthesized in vitro’, Cell, 8/2 (June 1976), 163-82.1976-06-01T00:00:00+00001979-01-01T00:00:00+0000Treatment given by Martin Cline to one patient in Israel and one in Italy. Cline criticised for failing to get secure permission from his Institutional Review Board at his home university - the University of California Los Angeles - and for not having sufficient animal data to show his method worked. 1980-01-01T00:00:00+0000The experiment was conducted by Oliver Smithies who adapted a gene-rescuing procedure developed by Goldfarb and colleagues to isolate a transforming gene from T24 bladder carcinoma cells. 1982-04-22T00:00:00+0000Murine leukaemia retrovirus genetically modified to produce the vector. R. Mann, R.C. Milligam, D. Baltimore, ‘Construction of a Retrovirus Packaging Mutant and Its Use to Produce Helper-Free Defective Retrovirus’, Cell, 33/1 (1983), 153-59.1983-05-01T00:00:00+0000Smithies, O, Koralewski, M A, Song, K Y, Kucherlapati, R S, 'Homologous recombination with DNA introduced into mammalian cells', Cold Spring Harbor symposia on quantitative biology, 49 (1984), 161-70.1984-01-01T00:00:00+00001985-01-22T00:00:00+0000Smithies, O, Gregg, R G, Boggs, S S, Koralewski, M A, Kucherlapati, R S, 'Insertion of DNA sequences into the human chromosomal beta-globin locus by homologous recombination', Nature, 317 (1985): 230-34.1985-09-19T00:00:00+0000Study conducted by French Anderson in collaboration with Steven Rosenberg in 52 year old cancer patient as preliminary experiment to test gene therapy in children with severe combined immunodeficiency disorder. 1989-05-01T00:00:00+0000G Gross, T Waks, Z Eshhar, 'Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity (chimeric genes/antibody variable region)', Proc Natl Acad Sci USA, 86 (1989), 10024-8.1989-12-01T00:00:00+0000G. Gross, T. Waks, Z. Eshhar, 'Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity', PNAS USA, 86 (1989), 10024–8.1989-12-01T00:00:00+0000A. Kasid et al, 'Human gene transfer: characterization of human tumor-infiltrating lymphocytes as vehicles for retroviral-mediated gene transfer in man', PNAS USA, 87/1 (1990), 473-77.1990-01-01T00:00:00+0000S.A. Rosenberg et al, 'Gene Transfer into Humans — Immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction', NEJM, 323 (1990), 570-78.1990-08-30T00:00:00+0000DeSilva treated by French Anderson in collaboration with Michael Blease1990-09-01T00:00:00+0000Procedure devised by Claudio Bordignon at Vita-Salute San Raffaele University, Milan. 1992-01-01T00:00:00+0000Z Eshhar, 'Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors', PNAS USA, 90/2 (1989), 720-24.1993-01-15T00:00:00+0000FDA publishes Application of Current Statutory Authorities to Human Somatic Cell Therapy Products and Gene Therapy Products.1993-10-14T00:00:00+0000Jesse Gelsinger, an 18 year old, died after suffering a severe immune response to an adenoviral vector in a dose escalation trial testing gene therapy for ornithine transcarbamylase deficiency, an inherited metabolic disorder. His death led to a major reappraisal of gene therapy and stricter regulations for clinical trials investigating gene therapy.1999-09-17T00:00:00+0000Treatment uses procedure devised by Bordignon.1999-12-01T00:00:00+0000Boys participating in multi-centre trial using procedure devised by Bordignon2000-01-01T00:00:00+0000Trials halted after French and UK children discovered to have developed leukaemia-like condition three years after receiving gene therapy for SCID. This found to be linked to the adenoviral vector used in their treatment.2002-01-01T00:00:00+0000Research conducted in US using a disabled HIV virus carrying a gene to inhibit replication. Trial is a success2003-01-01T00:00:00+0000The Chinese regulatory authority approved Gendicine from Shenzhen SiBiono GeneTech.2003-10-16T00:00:00+0000Urnov, F D, Miller, J C, Lee, Y, Beausejour, et al, 'Highly efficient endogenous human gene correction using designed zinc-finger nucleases', Nature, 435, (2005), 646–51.2005-04-03T00:00:00+0000R.A. Morgan et al, 'Cancer regression in patients after transfer of genetically engineered lymphocytes', Science. 2006;314:126–129.2006-10-06T00:00:00+0000M.H. Kershaw, et al, 'A Phase I Study on Adoptive Immunotherapy Using Gene-Modified T Cells for Ovarian Cancer', Clinical Cancer Research, 11/20 (2006), 6106-15.2006-10-15T00:00:00+00002007-01-01T00:00:00+0000Reik, A, Zhou, Y, Wagner, J, Hamlett, A, et al, 'Zinc finger nucleases targeting the glucocorticoid receptor allow IL-13 zetakine transgenic CTLs to kill glioblastoma cells in vivo in the presence of immunosuppressing glucocorticoids', Cancer Research, 68 (2008), 25572008-05-01T00:00:00+0000Perez, E E, Wang, J, Miller, J C , Jouvenot, Y, et al, 'Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases', Nature Biotechnology, 26 (2008): 808-16.2008-06-29T00:00:00+0000Corey Haas, receives gene therapy to replace a retinal pigment protein.2009-01-01T00:00:00+00002009-01-01T00:00:00+0000European Medicines Agency refuses market authorisation for Amsterdam Molecular Therapeutics's drug alipogene tiparvovec (Glybera)2010-01-01T00:00:00+0000Patient no longer needs blood transfusions for the blood disorder following insertion of corrected beta-globin gene into stem cells2010-01-01T00:00:00+0000J.N. Kochenderfer,et al, Blood, 116/20 (2010); M. Kalos, et al, Sci Tranl Med, 5 (2013), 95ra73; R.J. Brentijens et al, Science Translational Medicine, 5/177 (2013), 177ra882010-01-01T00:00:00+0000Gene therapy directed at liver cells2011-01-01T00:00:00+0000Allers, K, Hutter, G, Hofmann, J, Loddenkemper, C, Rieger, K, Thiel, E, et al,'Evidence for the cure of HIV infection by CCR5?32/?32 stem cell transplantation', Blood, 117/10, (2011): 2791–99.2011-03-10T00:00:00+0000The technique replaces genes in targeted organs without replacing cells from the body. The method uses zinc-finger nucleases. Li, H, Haurigot, V, Doyon, Y, Li, T, et al, 'In vivo genome editing restores haemostasis in a mouse model of hemophilia', Nature, 473 (2011), 217-21.2011-07-14T00:00:00+0000Intensive lobbying and political pressure for European Medicines Agency to consider approving the drug for an indication restricted to lipoprotein lipase–deficient patients who have experienced either severe or multiple pancreatitis attacks.2012-01-01T00:00:00+0000European Medicines Agency approves alipogene tiparvovec (Glybera) developed by Amsterdam Molecular Therapeutics and marketed by UniQure2012-07-01T00:00:00+0000Osborn, M J, Starker, C G, McElroy, A N, 'TALEN-based gene correction for epidermyolysis bullosa', Molecular Therapy, 21/6 (2013), 1151-9.2013-06-01T00:00:00+00002013-10-01T00:00:00+0000Treatment involved inserting a gene into the eye to revive light-detecting cells. Research led by Robert MacLaren based in the Nuffield Laboratory of Opthalmology.2014-01-01T00:00:00+0000Twelve patients with HIV treated between 2009 and 2014 report benefits from genetically engineered virus with a rare mutatiuon known to protect against HIV (CCR5 deficiency).2014-03-01T00:00:00+0000Tebas, T, Stein, D, Tang, W W, Frank, I, 'Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV', New England Journal of Medicine, 370/10 (2014): 901-10.2014-03-06T00:00:00+0000Yi et al, 'CCR5 Gene Editing of Resting CD4+ T Cells by Transient ZFN Expression From HIV Envelope Pseudotyped Nonintegrating Lentivirus Confers HIV-1 Resistance in Humanized Mice', Molecular Therapy Nucleic Acids, 3 (2014),:e198.2014-09-10T00:00:00+0000The application was submitted by Sangamo BioSciences. The therapy is based on a platform that uses zinc finger nucleases to replace a defective gene that causes haemophilia.2015-01-01T00:00:00+0000TALENs genome editing technique used to design immune cells to help treat baby, Layla Richards, with leukaemia. Work conducted by Paul Vehys and Waseem Qasim. 2015-11-05T00:00:00+0000The results suggest 'adenoviral delivery of zinc finger nucleases (ZFNs) to T-cells may be uniquely immune-stimulatory for both acute control of infection, and importantly, HIV reservoir reduction'. Sangamo Biosciences, Press release.2015-12-11T00:00:00+0000Nelson, C E, Hakim, C H, Ousterout, D G, Thakore, P I, et al, 'In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy', Science, DOI: 10.1126/science.aad51432015-12-31T00:00:00+0000LD Landegger et al, 'A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear', Nature Biotechnology, 6 Feb 2017, doi:10.1038/nbt.37812017-02-06T00:00:00+0000Patient treated with lentiviral vector-mediated addition of a gene into autologous hematopoietic stem cells. JA Ribell, S Hacien-Bey-Abina, E. OPayen, A. Magnani, et al, 'Gene therapy in a patient with sickle cell disease', NEJM, 376 (2017), 848-55.2017-03-02T00:00:00+0000The drug CTL019 (tisagenlecleucel) was developed by Novartis. Treatment involves removing T cells from the patient and genetically modifying them to increase their capacity to bind to tumour cells in order to get the immune sytem to attack the tumours. It is targeted at children and young adults from three to 25 years old who have not responded to traditional treatments.2017-07-12T00:00:00+0000The drug Kymriah (tisagenlecleucel) is the first gene therapy to become available in the US. 2017-08-30T00:00:00+0000Total of 17 boys treated in clinical trial, of which 15 showed marked improvement. Treatment used a modified form of HIV as the vector for infusing corrective genes to generate glial cells. F. Eichler, C. Duncan etl al, 'Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy', NEJM, DOI: 10.1056/NEJMoa17005542017-10-04T00:00:00+0000Treatment involved editing the patient's DNA using zinc finger nucleases technique. it was carried out on Brian Madeux, 44 year old man suffering from Hunter syndome, a metabolic disorder. Treatment was carried out by Paul Harmatz and his team at UCSF Benioff Children's Hospital. 2017-11-16T00:00:00+0000
Date Event People Places
16 Dec 1961First successful direct incorporation of functional DNA in human cellKrausUniversity of Tennessee
10 Dec 1966First evidence published suggesting a virus could provide delivery tool for transferring functional genesRogersOak Ridge National Laboratory
19 Oct 1968American scientists demonstrate that adding foreign genes to cultured cells from patients with Lesch-Nethan syndrome can correct genetic defects that cause the neurological diseaseFriedmann, SeegmillerNational Institutes of Health
1970 - 1975Three West German very young sisters fail to respond to first ever administered gene therapy Rogers, TerheggenOak Ridge National Laboratory, Cologne municipal hospital
3 Mar 1972First time gene therapy proposed as treatment for genetic disordersFriedmann, RoblinSalk Institute
June 1976First human disease gene, beta-globin, clonedManiatis, GekKee, Efstratiadis, Kafatos 
1979Beta-thalassemia gene successfully inserted into bone marrow of irradiated miceClineUniversity of California Los Angeles
1980Gene therapy unsuccessfully tried out in two patients with beta-thalaessemia sparks controversyClineUniversity of California Los Angeles
22 Apr 1982First experiment launched to test feasibility of inserting a corrective DNA in the right place in the human genomeSmithiesUniversity of Wisconsin
May 1983Creation of first retroviral vector suitable for gene therapyMann, Mulligan, BaltimoreMassachusetts Institute of Technology, Whitehead Institute for Biomedical Research
1984Experiment published demonstrating possibility of inserting a corrective DNA in the right place in genome of mammalian cellsSmithies, Koralewski, Song, KucherlapatiUniversity of Wisconsin
January 1985NIH publishes its first draft guidelines for proposing experiments in human somatic cell gene theray 
19 Sep 1985Technique published for the accurate insertion of a corrective DNA in the human genomeSmithies, Gregg, Boggs, Koralewski, KucherlapatiUniversity of Wisconsin
May 1989First human test demonstrated safety of retroviral vector for gene therapy and potential of laboratory produced tumor killing cells for cancer immunotherapyAnderson, RosenbergNational Institutes of Health
December 1989First use of genetically engineered T cells to redirect T cells to recognise and attack tumour cellsGross, Waks, EshharWeizmann Institute
December 1989Concept of enhancing T cells using chimeric antigen receptors published for first timeGross, Waks, EshharWeizmann Institute
January 1990Gene therapy concept proven in first human trialsKasid, Morecki, Aebersold, Cornetta, Culver, Freeman, Director, Lotze, Blaese, AndersonNational Cancer Institute
30 Aug 1990Treatment with gene modified tumour-infiltrating lymphocytes shown to be promising immunotherapy for patients with advance melanomaRosenberg, Aebersold, Cornetta, Kasid, Morgan, Moen, Karson, Lotze, Yang, Topalian, Merino, Culver, Miller, Blaese, AndersonNational Cancer Institute
September 1990Four year old Ashanti DeSilva becomes first patient successfully treated with gene therapy for severe combined immunodeficiency caused by defective ADA geneAnderson, Blease, DeSilvaNational Institutes of Health
1992Stem cells used as vectors to deliver the genes needed to correct the genetic disorder SCIDBordignonVita-Salute San Raffaele University
15 Jan 1993Chimeric receptor genes added to T lymphocytes shown to enhance power of adoptive cellular therapy against tumoursEshhar, Waks, Gross, SchindlerWeizmann Institute
October 1993FDA lays out regulations governing gene therapy 
September 1999Death of the first patient in a gene therapy trial prompts major setback for the fieldGelsinger, WilsonUniversity of Pennsylvania
1999 - 2002Multi-centre trials with gene therapy using stem cells to treat children with SCIDBordignon 
2000Two French boys suffering from SCID reported to be cured using gene therapy 
1 Jan 2002Suspension of French and US gene therapy trials for treating SCID children 
1 Jan 2003First human trial of gene therapy using modified lentivirus as a vector 
October 2003China 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 2005Zinc 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 disordersUrnov, Miller, Lee, BeausejourSangamo BioSciences, University of Texas Southwester Medical Center
6 Oct 2006Genetically engineered lymphocytes shown to be promising cancer treatmentMorgan, Dudley, Wunderlich, Hughes, Yang, Sherry, Royal, Topalian, Kammula, Restifo, Zheng, Nahvi Vries, Rogers-Freezer, Mavroukakis, RosenbergNational Cancer Institute
15 Oct 2006Adoptive cellular therapy using chimeric antigen receptor T cells shown to be safe in small group of patients with ovarian cancerKershaw, Westwood, Parker, Wang, Eshhar, Mavroukakis, White, Wunderlich, Canevari, Rogers-Freezer, Chen, Yang, Rosenberg, HwuNational Cancer Institute, University of Melbourne, M.D. Anderson Cancer Center, Weizmann Institute, Istituto Nazionale Tumori
2007Small trial published demonstrating possibility of using gene therapy for inherited retinal diseaseBennettUniversity of Pennsylvania
1 May 2008Zinc finger method explored as means to develop treatment for glioblastoma (brain tumour)Reik, Zhou, Wagner, HamlettSangamo BioSciences
29 Jun 2008Zinc finger method used to make HIV-resistant CD4 cells to develop immunotherapy for HIV Perez, Wang, Miller, JouvenotAbramson Family Cancer Research Institute, Children's Hospital of Philadelphia, Sangamo BioSciences, Bayer
2009Almost blind child with rare inherited eye disease gains normal vision following gene therapy 
2009Gene therapy halts progression of degenerative disease adrenoleukodystrophy in two boys 
January 2010Gene therapy for treatment of lipoprotein lipase deficiency fails to win European approvalAmsterdam Molecular Therapeutics, UniQure
January 2010Gene therapy successful in treating beta-thalassaemia 
2010 - 2013Studies show CD19-specific CAR-modified T cells to be promising treatment in patients with B cell malignanciesKochenderfer, Kalos, BrentjensNational Cancer Institute, National Institutes of Health, Memorial Sloan-Kettering Cancer Center, University of Pennsylvania
1 Jan 2011Gene therapy reduces symptoms in six patients with haemophilia B 
10 Mar 2011Patient 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-1Allers, Hutter, Hofmann, Loddenkemper, RiegerCharite-University Medicine Berlin
14 Jul 2011Gene repair kit used successfully to treat blood-clotting disorder haemophilia in miceLi, Haurigot, Doyon, HighChildren's Hospital Philadelphia, Sangamo Biosciences, University of Philadelphia
January 2012European Union asks European Medicines Agency to reconsider approval of alipogene tiparvovecAmsterdam Molecular Therapeutics, UniCure
July 2012First gene therapy approved for treatment of patients with familial lipoprotein lipase deficiencyAmsterdam Molecular Therapeutics
1 Jun 2013Basic studies conducted with TALENs to see if can correct mutant genes associated with Epidermolysis Bullosa, a rare inherited skin disorderOsborn, Starker, Colby, McElroyUniversity of Minnesota, National Centre for Tumor Diseases Heidelberg, German Cancer Research Centre, Harvard University
October 2013Fiven children with ADA-SCID successfully treated with gene therapy 
January 2014Eyesight reported to improve in six patients suffering from choroideremia after receiving gene therapyMacLarenOxford University
March 2014Promising results announced from trial conducted with HIV patients 
6 Mar 2014Phase I trial using Zinc finger nuclease modified CD4 cells to treat 12 HIV patients shows the approch is safe.Tebas, Stein, Tang, FrankUniversity of Pennsylvania
10 Sep 2014Mice trials show CD4 T-cells genetically modified with Zinc fingers could be effective HIV-1 gene therapy Yi, Choi, Bharaj, AbrahamTexas Tech University, University of North Carolina
1 Jan 2015US 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 clinicEwing, ZaiaSangamo Biosciences, City of Hope National Medical Center
5 Nov 2015First report of successful use of gene therapy to treat leukaemiaVehs, QuasimGreat Ormond Street
11 Dec 2015Preliminary results presented for phase 2 trial using Zinc finger nuclease modified CD4 and CD8 cells to treat HIV patients Sangamo Biosciences
31 Dec 2015CRISPR 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 patientsNelson, Gersbach, Hakim, Ousterout, ThakoreDuke University, University of Missouri, University of North Carolina, Massachusetts Institute of Technology, Harvard University
6 Feb 2017Gene therapy shown to restore hearing in deaf miceLandegger, Pan, Askew, Wassmer, Gluck, Galvin, Taylor, Forge, Sankovic, Holt, VandenbergheEaton 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 2017Gene therapy reported to successfully reverse sickle cell disease in first patientRibell, Hacien-Bey-Abina, Payen, Magnani, LeboulchUniversity of Paris
12 Jul 2017US FDA Oncologic Drugs Advisory Committee recommended the approval of the first adoptive cell therapy (CAR-T cell therapy) for B cell acute leukaemiaNovartis, University of Pennsylvania
30 Aug 2017USA FDA approved CAR-T therapy for certain pediatric and young adult patients with a form of acute lymphoblastic leukemiaNovartis, University of Pennsylvania
4 Oct 2017Gene therapy shown in clinical trials to halt progression of adrenoleukodystrophy, a fatal brain disease inherited by boys Eichler, Duncan, WilliamsHarvard University, Bluebird Bio, Boston Children’s Hospital
16 Nov 2017First patient receives therapy involving gene editing inside the bodyHarmatz, MadeuxUniversity 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

Jun 1976

First human disease gene, beta-globin, cloned

1979

Beta-thalassemia gene successfully inserted into bone marrow of irradiated mice

1980

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

May 1983

Creation of first retroviral vector suitable for gene therapy

1984

Experiment published demonstrating possibility of inserting a corrective DNA in the right place in genome of mammalian cells

Jan 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

May 1989

First human test demonstrated safety of retroviral vector for gene therapy and potential of laboratory produced tumor killing cells for cancer immunotherapy

Dec 1989

First use of genetically engineered T cells to redirect T cells to recognise and attack tumour cells

Dec 1989

Concept of enhancing T cells using chimeric antigen receptors published for first time

Jan 1990

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

Sep 1990

Four year old Ashanti DeSilva becomes first patient successfully treated with gene therapy for severe combined immunodeficiency caused by defective ADA gene

1992

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

Oct 1993

FDA lays out regulations governing gene therapy

Sep 1999

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

2000

Two French boys suffering from SCID reported to be cured using gene therapy

2000

Suspension of French and US gene therapy trials for treating SCID children

2000

First human trial of gene therapy using modified lentivirus as a vector

Oct 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

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

2007

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

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

Jan 2010

Gene therapy for treatment of lipoprotein lipase deficiency fails to win European approval

Jan 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

2010

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

Jan 2012

European Union asks European Medicines Agency to reconsider approval of alipogene tiparvovec

Jul 2012

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

Oct 2013

Fiven children with ADA-SCID successfully treated with gene therapy

Jan 2014

Eyesight reported to improve in six patients suffering from choroideremia after receiving gene therapy

Mar 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.

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