Gene Therapy History

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. When the first gene therapy was approved in the United States there were 854 companies developing such therapies. According to the Alliance for Regenerative Medicine there were 1085 companies in that space by the end of 2020 and more than 400 gene therapy trials under way.

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 [Dr. Paul Berg (born 1926)] 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 [Dr. William French Anderson (born 1936)], 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 [Dr. Robert Michael Blaese (born 1939)], 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 [Dr. Steven Aaron Rosenberg (born 1940) ] 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. The drug, however, failed to be a commercial success because too few patients needed the drug. This led to UniQure withdrawing marketing authorisation for the drug by 2017.

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 in January 2018. 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

Date

Event

People

Places

22 Nov 1912

Paul Zamecnik was born in Cleveland, Ohio, USA

Zamecnik

Massachusetts General Hospital

16 Oct 1943

Roland Levinsky was born in Bloemfontein, South Africa

Levinsky

Great Ormond Street Hospital, Institute of Child Health, University College London

16 Dec 1961

First successful direct incorporation of functional DNA into a human cell

Kraus

University of Tennessee

10 Dec 1966

First evidence published suggesting a virus could provide delivery tool for transferring functional genes

Rogers

Oak Ridge National Laboratory

19 Oct 1968

American scientists demonstrate that adding foreign genes to cultured cells from patients with Lesch-Nethan syndrome can correct genetic defects that cause the neurological disease

Friedmann, Seegmiller

National Institutes of Health

1970 - 1975

Three West German very young sisters fail to respond to first ever administered gene therapy

Rogers, Terheggen

Oak Ridge National Laboratory, Cologne municipal hospital

3 Mar 1972

First time gene therapy proposed as treatment for genetic disorders

Friedmann, Roblin

Salk Institute

June 1976

First human disease gene, beta-globin, cloned

Maniatis, GekKee, Efstratiadis, Kafatos

1979

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

Cline

University of California Los Angeles

1980

Gene therapy unsuccessfully tried out in two patients with beta-thalaessemia sparks controversy

Cline

University of California Los Angeles

22 Apr 1982

First experiment launched to test feasibility of gene targeting in the human genome

Smithies

University of Wisconsin

May 1983

Creation of first retroviral vector suitable for gene therapy

Mann, Mulligan, Baltimore

Massachusetts Institute of Technology, Whitehead Institute for Biomedical Research

1984

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

Smithies, Koralewski, Song, Kucherlapati

University of Wisconsin

22 Jan 1985

NIH published its first draft guidelines for proposing experiments in human somatic cell gene theray

19 Sep 1985

Technique published for the accurate insertion of a corrective DNA in the human genome

Smithies, Gregg, Boggs, Koralewski, Kucherlapati

University of Wisconsin

May 1989

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

Anderson, Rosenberg

National Institutes of Health

December 1989

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

Gross, Waks, Eshhar

Weizmann Institute

December 1989

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

Gross, Waks, Eshhar

Weizmann Institute

January 1990

Gene therapy concept proven in first human trials

Kasid, Morecki, Aebersold, Cornetta, Culver, Freeman, Director, Lotze, Blaese, Anderson

National Cancer Institute

30 Aug 1990

Treatment with gene modified tumour-infiltrating lymphocytes shown to be promising immunotherapy for patients with advance melanoma

Rosenberg, Aebersold, Cornetta, Kasid, Morgan, Moen, Karson, Lotze, Yang, Topalian, Merino, Culver, Miller, Blaese, Anderson

National Cancer Institute

September 1990

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

Anderson, Blease, DeSilva

National Institutes of Health

1992

Stem cells used as vectors to deliver the genes needed to correct the genetic disorder SCID

Bordignon

Vita-Salute San Raffaele University

15 Jan 1993

Chimeric receptor genes added to T lymphocytes shown to enhance power of adoptive cellular therapy against tumours

Eshhar, Waks, Gross, Schindler

Weizmann Institute

14 Oct 1993

FDA published its regulations governing gene therapy

17 Sep 1999

Death of the first patient in a gene therapy trial prompted major setback for the field

Gelsinger, Wilson

University of Pennsylvania

1999 - 2002

Multi-centre trials with gene therapy using stem cells to treat children with SCID

Bordignon

2000

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

2 Jan 2000

Polyoma virus shown to be potential tool for delivering gene therapy

Krauzewicz, Stokrova, Jenkins, Elliott, Higgns, Griffin

Imperial College, Czech Academy of Sciences, University of Wales

1 Jan 2002

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

1 Jan 2003

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

16 Oct 2003

China approved the world's first commercial gene therapy

3 Apr 2005

Zinc finger method reported capable of modifying some genes in the human genome, laying the foundation for its use as tool to correct genes for monogenic disorders

Urnov, Miller, Lee, Beausejour

Sangamo BioSciences, University of Texas Southwester Medical Center

6 Oct 2006

Genetically engineered lymphocytes shown to be promising cancer treatment

Morgan, Dudley, Wunderlich, Hughes, Yang, Sherry, Royal, Topalian, Kammula, Restifo, Zheng, Nahvi Vries, Rogers-Freezer, Mavroukakis, Rosenberg

National Cancer Institute

15 Oct 2006

Adoptive cellular therapy using chimeric antigen receptor T cells shown to be safe in small group of patients with ovarian cancer

Kershaw, Westwood, Parker, Wang, Eshhar, Mavroukakis, White, Wunderlich, Canevari, Rogers-Freezer, Chen, Yang, Rosenberg, Hwu

National Cancer Institute, University of Melbourne, M.D. Anderson Cancer Center, Weizmann Institute, Istituto Nazionale Tumori

2007

Small trial published demonstrating possibility of using gene therapy for inherited retinal disease

Bennett

University of Pennsylvania

1 May 2008

Zinc finger method explored as means to develop treatment for glioblastoma (brain tumour)

Reik, Zhou, Wagner, Hamlett

Sangamo BioSciences

29 Jun 2008

Zinc finger method used to make HIV-resistant CD4 cells to develop immunotherapy for HIV

Perez, Wang, Miller, Jouvenot

Abramson Family Cancer Research Institute, Children's Hospital of Philadelphia, Sangamo BioSciences, Bayer

2009

Almost blind child with rare inherited eye disease gains normal vision following gene therapy

2009

Gene therapy halts progression of degenerative disease adrenoleukodystrophy in two boys

11 Feb 2009

Stem-cell transplant reported to be promising treatment for curing HIV

Hutter

University of Berlin

27 Dec 2009

Paul Zamecnik died

Zamecnik

Massachusetts General Hospital

January 2010

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

Amsterdam Molecular Therapeutics, UniQure

January 2010

Gene therapy successful in treating beta-thalassaemia

2010 - 2013

Studies show CD19-specific CAR-modified T cells to be promising treatment in patients with B cell malignancies

Kochenderfer, Kalos, Brentjens

National Cancer Institute, National Institutes of Health, Memorial Sloan-Kettering Cancer Center, University of Pennsylvania

14 Jan 2010

Research published suggesting gene therapy could help preserve neural circuits and protect against vision loss in patients with multiple sclerosis

Dorothy Schafer, Werneburg, Jung, Kunjama

University of Massachusetts Medical School, University of Chicago, National Institute of Neurological Disorders and Stroke, University of Connecticut School of Medicine

1 Jan 2011

Gene therapy reduces symptoms in six patients with haemophilia B

10 Mar 2011

Patient suffering from acute myeloid leukaemia is cured of HIV-1 after receiving bone marrow stem cells transplanted from donor with mutated CCR5 gene. This awakens interest in developing HIV treatment that renders a patient's cells resistant to HIV-1

Allers, Hutter, Hofmann, Loddenkemper, Rieger

Charite-University Medicine Berlin

14 Jul 2011

Gene repair kit used successfully to treat blood-clotting disorder haemophilia in mice

Li, Haurigot, Doyon, High

Children's Hospital Philadelphia, Sangamo Biosciences, University of Philadelphia

January 2012

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

Amsterdam Molecular Therapeutics, UniCure

July 2012

First gene therapy approved for treatment of patients with familial lipoprotein lipase deficiency

Amsterdam Molecular Therapeutics

1 Jun 2013

Basic studies conducted with TALENs to see if can correct mutant genes associated with Epidermolysis Bullosa, a rare inherited skin disorder

Osborn, Starker, Colby, McElroy

University of Minnesota, National Centre for Tumor Diseases Heidelberg, German Cancer Research Centre, Harvard University

October 2013

Fiven children with ADA-SCID successfully treated with gene therapy

January 2014

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

MacLaren

Oxford University

March 2014

Promising results announced from trial conducted with HIV patients

6 Mar 2014

Phase I trial using Zinc finger nuclease modified CD4 cells to treat 12 HIV patients shows the approch is safe.

Tebas, Stein, Tang, Frank

University of Pennsylvania

10 Sep 2014

Mice trials show CD4 T-cells genetically modified with Zinc fingers could be effective HIV-1 gene therapy

Yi, Choi, Bharaj, Abraham

Texas Tech University, University of North Carolina

1 Jan 2015

US FDA cleared Investigative Drug Application for clinical trial of gene therapy for haemophila B. The therapy was the first in vivo genome editing application to enter the clinic

Ewing, Zaia

Sangamo Biosciences, City of Hope National Medical Center

21 Jul 2015

Phase 1 clinical trial launched with RNAi treatment for Huntingdon's disease

Isis Pharmaceuticals, Roche

October 2015

First oncology gene therapy approved in US and Europe

Amgen

5 Nov 2015

First successful use of gene therapy to treat baby dying from leukaemia

Vehs, Quasim

Great Ormond Street

11 Dec 2015

Preliminary results presented for phase 2 trial using Zinc finger nuclease modified CD4 and CD8 cells to treat HIV patients

Sangamo Biosciences

31 Dec 2015

Gene editiing tool, CRISPR, successfully used to improve muscle function in mouse model of Duchenne muscular dystrophy

Nelson, Gersbach, Hakim, Ousterout, Thakore

Duke University, University of Missouri, University of North Carolina, Massachusetts Institute of Technology, Harvard University

21 Jun 2016

2016: NIH gives green light for first clinical trial using gene editing tool CRISPR/Cas 9 to treat patients

June

University of Pennsylvania

6 Feb 2017

Gene therapy shown to restore hearing in deaf mice

Landegger, Pan, Askew, Wassmer, Gluck, Galvin, Taylor, Forge, Sankovic, Holt, Vandenberghe

Eaton Peabody Laboratories, Harvard Medical School, Medical University of Vienna, UCL, Boston's Children's Hospital, Harvard Stem Cell Institute, University of North Carolina, Grousbeck Gene Therapy Center

2 Mar 2017

Gene therapy reported to successfully reverse sickle cell disease in first patient

Ribell, Hacien-Bey-Abina, Payen, Magnani, Leboulch

University of Paris

April 2017

First gene therapy approved in Europe for lipoprotein lipase deficiency (Glybera) withdrawn from market

uniQure

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

June

Novartis, University of Pennsylvania

30 Aug 2017

USA FDA approved CAR-T therapy for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia

June

Novartis, University of Pennsylvania

4 Oct 2017

Gene therapy shown in clinical trials to halt progression of adrenoleukodystrophy, a fatal brain disease inherited by boys

Eichler, Duncan, Williams

Harvard University, Bluebird Bio, Boston Children’s Hospital

16 Nov 2017

First patient received therapy involving gene editing inside the body

Harmatz, Madeux

University of California San Francisco

9 Dec 2017

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

Rangarajan, Walsh, Lester, Perry, Madan, Laffan, Hua Yu, Vettermann, Pierce, Wong, Pasi

Barts Health NHS Trust, Queen Mary University, BioMarin Pharmaceutical

19 Dec 2017

US FDA approved gene therapy approved to treat rare genetic retinal disease

Novartis, Spark Therapeutics

5 Jan 2018

Researchers identify pre-existing antibodies targeting CAS9 proteins raising possibility of immune responses undermining utility of CRISPR-Cas9 for gene therapy

Charlesworth, Deshpande, Dever, Dejene,Gomez-Ospina, Mantri, Pavel-Dinu, Camarena, Weinberg, Porteus

Stanford University

19 Apr 2018

Gene therapy shown to be promising treatment in clinical trials for beta thalassemia

Thompson, Walters, Kwiatkowski, Rasko, Ribeil, Hongeng, Magrin, Schiller, Payen, Smeraro, Moshous, Lefrer

North Western University, University of California San Francisco, University of California Los Angeles, University of Sydney, University of Paris, Harvard University, Mahidol University, German Cancer Research Centre

27 Aug 2018

First CRISPR-Cas9 clinical trial launched

Vertex Pharmaceuticals, CRSIPR Therapeutics

23 Nov 2018

Gene therapy approved in Europe for treatment of patients with vision loss linked to genetic mutation

Novartis, Spark Therapeutics

5 Mar 2019

Second patient reported free of HIV after receiving stem-cell therapy

Gupta

University of Cambridge

19 Apr 2019

Gene therapy shown to be promising in treating infants born with X-linked severe combined immunodeficiency (SCID-X1)

Mamcarz, Zhou, Lockey, Abdelsamed, Cross, Kang, Ma, Condori, Dowdy, Triplett, Maron

St. Jude Children’s Research Hospital

22 Jan 2020

Mice experiments indicate gene therapy could provide long-lasting protection against different chemical nerve agents

Betapudi, Goswami, Silayeva, Doctor, Chilukuri

US Army Medical Research Institute of Chemical Defense

4 Mar 2020

First patient received gene editing therapy with CRISPR directly administered into the body

Pennesi

Oregon Health and Science University

12 May 2021

Gene therapy reported to restore immune function in children with rare immunodeficiency

Donald Kohn, Claire Booth

University of California Los Angeles, Great Ormond Street Hospital

24 May 2021

Gene therapy reported to restore partial vision to blind person

Sahel, Boulanger-Scemama, Pagot, Arleo, Galluppi, Martel, Degli, Delaux, de Saint Aubert, De Montleau, Gutman, Audo, Duebel, Picaud, Dalkara, Blouin, Taiel, Roska

Sorbonne University, University of Pittsburgh, GenSight Biologics

25 May 2021

First NHS patient treated with gene therapy for spinal muscular atrophy

Novartis, Evelina London Children's Hospital