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

Gene therapy gained a lot of commercial interest in the 1980s. In part this was because many assumed such treatment would move swiftly and easily from proof of concept into clinical trials. Such hopes, however, were dashed following the death of the first patient in a gene therapy trial in 1999. It would take another decade before optimism about the therapy resurfaced. From 2008 onwards dozens of new start-ups began to be created around gene therapy. These were founded on the back of sponsorship from pharmaceutical companies and the stock market. Just how much weight began to be 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 demonstrated the feasibility of incorporating new genetic functions in mammalian cells in the late 1960s. Several methods were used. One involved injecting genes with a micropipette directly into a living mammalian cell. Another exposed cells to a precipitate of DNA containing the desired genes. A virus could also 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 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. Seven years later, Theodore Friedmann, Jay Seegmiller and John Subak-Sharpe at the National Institutes of Health (NIH), Bethesda, successfully corrected 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.

The first humans to receive gene therapy took place in 1970. It was administered to 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 sister received an injection of a rabbit virus (Shope papilloma) known to induce the production of arginase. The injection was given as a last desperate measure to rescue the children. The treatment was carried out by Stanfield Rogers, an American physician, together with H. G. Terheggen, a German paediatrician. They took the risk based on observations Rogers had previously made with some laboratory technicians at Oak Ridge National Laboratory who became infected with the rabbit virus when working with it. None of the technicians experienced ill-effects from the virus but had abnormally low levels of arginine in their blood. This was apparent even in a technician whose last exposure to the virus had been 20 years before. Rogers connected the technicians’ abnormal arginine levels with a gene in the rabbit virus which was known to encourage the production of arginase in rabbits. By giving the rabbit virus to the girls, Rogers hoped to transfer genetic instructions to their cells to produce arginase. After the two sisters were treated a third sister was born afflicted with hyperargininemia. She was also injected with the virus. Disappointingly none of the sisters responded to the treatment.

A new pathway for gene therapy opened up with the development of genetic engineering 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. The potential of the technology for gene therapy was first highlighted by the US scientists Theodore Friedmann and Richard Roblin. In 1972 they published an article in Science suggesting genetically modified tumour viruses might be used to transfer the necessary genetic information to treat genetic disorders in patients.

The technique was first tried out in the case of beta-thalassemia. Linked to an inherited defect in a gene for beta-globin, this blood disorder usually causes premature death. The beta-globin gene was first cloned by scientists at Cold Spring Harbor Laboratory and Harvard University in 1976. It was the first disease gene ever 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. Following this, Cline and his team unsuccessfully tried to treat two beta-thalassemia patients, one in Italy and another in Israel by inserting the gene into bone marrow extracted from them and then reinfusing the cells. Cline was immediately reprimanded for failing to secure the necessary permission from his home institution’s Institutional Review Board to carry out the work and having insufficient animal data to demonstrate the effectiveness of his procedure. The incident cost Cline his university chair and most of his funding from the NIH. It also ignited a furious public debate about the social and ethical implications of gene therapy. This led to the tightening up of regulations for the future testing of gene therapy in humans, which were to be overseen by the NIH’s Recombinant DNA Advisory Committee (RAC).

Gene therapy entered a new era in the 1980s following the discovery of retroviruses which proved a much more efficient tool for gene transfer. The first suitable retroviral vector for gene therapy was developed by Richard Mulligan, a researcher at Massachusetts Institute of Technology and former doctoral student of Paul Berg, a key pioneer in genetic engineering at Stanford University. By 1983 Mulligan had managed to genetically modify a mouse leukemia retrovirus with his colleagues so that it could deliver any desired DNA without reproducing in humans. The new 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.

One of the first people to use Mulligan’s new vector was French Anderson, a geneticist at the NIH’s National Heart, Lung and Blood Institute. By 1989 he had secured permission from the RAC to begin the first approved clinical trial with gene therapy. This was to be done with the help of Michael Blease, a paediatrician and immunologist. The team’s aim was to test gene therapy in children with severe combined immunodeficiency, an inherited immune disorder caused by a defective adenosine deaminase (ADA) 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 with 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 and the risks of an immune reaction. The second was to have frequent injections of PEG-ADA, a synthetic enzyme. Children who had such treatment usually showed a marked improvement after the first injection but this was usually of short duration and subsequent doses were largely ineffective.

Prior to treating the children the team partnered with Steven Rosenberg at the National Cancer Institute (NCI) conducted a test of their proposed procedure in a 52 year old man dying from malignant melanoma in May 1989. This was designed to assess three things: assess the safety of Mulligan’s retroviral vector, determine how much of the marked gene it could transfer and how long the gene lasted. The experiment involved a number of stages. In the first instance, the scientists needed to cultivate tumour infiltrating lymphocytes (TIL cells), a type of tumour-killing cell. This involved incubating white blood cells removed from the man’s tumour with interleukin-2, a molecule found to activate T in the destruction of cancer cells in the 1960s. A DNA marker was then inserted into the TIL cells before they were reinfused into the patient. The same procedure was repeated in seven more patients at the NCI with terminal malignant melanoma. Encouragingly all of the patients absorbed the marker genes with no ill-effects and a third of them responded positively to the treatment. 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 door to the development of gene therapy for cancer.

Anderson’s team started trying out the gene therapy in children with ADA-SCID in early 1990. The first patient to receive the therapy was Ashanti DeSilva, a four year old girl. Her treatment lasted twelve days. It necessitating extracting Ashanti’s blood cells, inserting a new working copy of the ADA gene into them and then reinfusing the cells into her. Overall, the procedure was similar to a bone marrow transplant. The goal was to replenish Ashanti’s blood cells with ones that could produce ADA. Gene therapy had the advantage that the cells originated from Ashanti so there was no risk of rejection. To everyone’s delight 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 light 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. Most of the trials targeted cancer, but cardiovascular disease, AIDS, cystic fibrosis and Gaucher disease were also investigated.

Some of the early enthusiasm for gene therapy witnessed at the beginning of the decade, however, had begun to disappear by the end of the 1990s. This was because researchers struggled to get the therapy to work because of the inefficiency of the retroviral vectors they had to hand. Negative attitudes to gene therapy increased following the first death in a trial. In September 1999, Jesse Gelsinger, an 18 year old American died while taking part as a volunteer in a dosing escalation trial. Led by James M Wilson, the trial was designed to treat newborn infants with a fatal inherited a metabolic disorder, known as ornithine transcarbamylase deficiency, which leads to the buildup of excessive ammonia in the body. Gelsinger had himself been born with the condition, but had managed to keep it in check by restricting his diet and taking special medications. He was allocated to the last group in the trial who received the highest dose. Four days after treatment Gelsinger died from major organ failure because of 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. One of the reasons such a virus was used was because such viruses were well characterised and had a small genome so were easy to manipulate. Moreover, most people carry adenoviruses without experiencing any significant clinical symptoms. Investigations into Gelsinger’s death revealed insufficient care had been taken during the trial and poor clarity in terms of its safety guidelines.

While the tragedy led to the enforcement of more stringent regulations for gene therapy trials, Gelsinger 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 discovered 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. Their cancer turned out to have been caused by an adenoviral vector that integrated into a part of their genome that activated a gene for leukaemia. This too the scientists by total surprise because most adenoviruses are unable to integrate into the host genome.

Despite the difficulties, gene therapy began to turn a corner the following decade, aided by the arrival of safer and more effective vectors. Positive results began to be reported for a number of gene therapy trials. Most were small-scale academic studies. In 2007 Jean Bennett, an ophthalmologist at the University of Pennsylvania, demonstrated in a small trial that gene therapy could provide a promising treatment for inherited retinal disease. Subsequent trials in more patients carried out in 2015 backed this up. In addition to eye disease, gene therapy was found to help haemophilic patients, a number of whom no longer needed to take blood clotting factor drugs. Good news also emerged in 2015 from trials of gene therapy for rare single-mutation blood diseases like thalassemia and sickle-cell anaemia, with some patients able to stay healthy without blood transfusions. A year later, two small trials showed gene therapy could help in the treatment of patients with cerebral adrenoleukodystrophy, an inherited disorder that affects the central nervous system, and with 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 neck and head cancer, this treatment did not make it across to other countries. The first gene therapy was approved in Europe nine years later. It was developed by UniQure, a Dutch company for treating lipoprotein lipase deficiency, a rare metabolic disease that causes acute and recurrent abdominal pain and inflammation of the pancreas. In 2016 Europe licensed a second gene therapy, developed by GlaxoSmithKline for children suffering from ADA-SCID. A year later Novartis secured approval for the first gene therapy in the United States. Designed to treat acute lymphoblastic leukaemia, the therapy had grown out of the preliminary work Anderson and Rosenberg had originally undertaken to establish the safety of gene therapy for treating children with ADA-SCID in 1989.

Application

Gene therapy takes different forms. It can involve the insertion of a copy of a new gene, modifying or inactivating a gene, or correcting a gene mutation. This is done with the help of a vector derived from a genetically modified virus. Several different viral vectors are now used for this purpose.

Adenoviral vectors are some of the most common ones. These vectors work best in nondividing cells such as found in the brain or retina. Lentiviral vectors are also popular. These are derived from lentiviruses, a group of retroviruses. Two of the most commonly used, which emerged in the late 1990s, are the human immunodeficiency virus and the herpes simplex virus. Such vectors have the advantage that they can carry large quantities of genes and work in non-dividing cells. Nonetheless, they, present some safety issues because it is difficult to predict where they will integrate into the host genome. For this reason, lentiviral vectors are generally deployed in the genetic alteration of cells extracted from patients. Lentiviral vectors are particularly helpful in the introduction of genes into the genome of cells that are generally difficult to modify. Lentiviral vectors made from the herpes simplex virus are currently being used in gene therapies being explored for pain and brain diseases.

New horizons have opened up for gene therapy with the recent development of CRISPR-Cas9, a much more precise technique for altering genes. At the end of 2016 a group of Chinese scientists, led by the oncologist Lu You at Sichuan University, launched 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 2017, a similar trial was initiated by an American team headed by Carl June at the University of Pennsylvania.

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 has been administered it is difficult to stop treatment. It is also too early to know how long the effects of a gene therapy 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 that so far the price of gene therapy has been incredibly high. Gene therapies are currently some of the most expensive treatments on the market. In part this reflects the fact that most of them are custom-made for 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, October 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+0000Patients with severe haemophilia A received a single infusion of a copy of a missing gene that allows their cells to produce Factor VIII, a protein needed to stop bleeding. This was delivered using an adeno-associated virus vector. The patients were enrolled between September 2015 and April 2016 into one of three dose cohorts at five sites across the UK. The five UK trial sites included: The Royal London, Guys and St Thomas', Birmingham, Cambridge and Hampshire hospitals. At 54 week follow-up 85% of the patients were found to have normal or near normal Factor VIII levels. Thirteen of the patients no longer needed their previously regular treatment. S. Rangarajan, et al, 'AAV5–Factor VIII Gene Transfer in Severe Hemophilia A', New England Journal of Medicine (9 Dec 2017), DOI: 10.1056/NEJMoa1708483.2017-12-09T00:00:00+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
9 Dec 2017Gene therapy shown to be safe and efficacious treatment for haemophilia A in British trialsRangarajan, Walsh, Lester, Perry, Madan, Laffan, Hua Yu, Vettermann, Pierce, Wong, PasiBarts Health NHS Trust, Queen Mary University, BioMarin Pharmaceutical

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

9 Dec 2017

Gene therapy shown to be safe and efficacious treatment for haemophilia A in British trials