History of Gene Therapy

The exciting field of gene therapy 50 years in the making.

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1970
Gene Therapy Concept Established

Gene Therapy Concept Established

In 1970, Dr. Rogers thought that “good” DNA could be used to replace defective DNA in individuals with genetic disorders. He tried this idea out on two girls in Germany who were suffering from a genetic disorder called argininemia but his attempt was unsuccessful. This was thought to be due to the instability of the virus, which underwent a rigorous purification procedure and failed to stimulate arginase induction.1,2

In 1972, Dr. Friedmann and Dr. Roblin published the paper “Gene therapy for human genetic disease” in Science and the authors encouraged Dr. Rogers to proceed with caution. The authors proposed that a complete set of ethico-scientific criteria be developed to guide the clinical application of gene therapy to ensure the beneficial use of this therapy and prevent misuse through premature application.3

1989
First approved clinical trial protocol to use gene transfer into humans

First approved clinical trial protocol to use gene transfer into humans

First approved clinical trial protocol to use retroviral-mediated gene transduction to introduce a marker gene into human tumor-infiltrating lymphocytes (TILs) before their infusion back into five patients with advanced melanoma4.

Demonstrated the feasibility and safety of using retroviral-mediated gene transduction as a method of introducing new genes into the body for human gene therapy4.

1990
First clinical trial to deliver a therapeutic gene (ex vivo, retroviral vector)

First clinical trial to deliver a therapeutic gene (ex vivo, retroviral vector)

In 1990, the first clinical trial to deliver a therapeutic gene was conducted.5 A gamma-retroviral vector was used to mediate the transfer of the gene encoding adenosine deaminase (ADA) into the T cells of two children suffering from severe combined immunodeficiency (SCID)6, a rare condition caused by loss-of-function mutations in the genes encoding the interleukin-2 receptor gamma subunit or ADA.7,8 Authors concluded that gene therapy was a safe and effective treatment for some patients with this severe immunodeficiency disease.6

In the late 1990s and early 2000s, trials continued to demonstrate unequivocal improvement in immune function in patients with SCID. However, several years after treatment, patients in the X-linked SCID trials, as well as those for chronic granulomatous disease and Wiskott–Aldrich syndrome, developed acute myeloid and lymphoid leukemias; this was due to activation of proto-oncogenes adjacent to proviral insertions, which were linked to strong enhancers present in gamma-retroviral vectors, and the propensity of these vectors to insert near promoters.7

1999
Death of a clinical trial participant due to severe immune reaction following in vivo adenoviral vector administration

Death of a clinical trial participant due to severe immune reaction following in vivo adenoviral vector administration

On September 17, 1999, 18-year-old American Jesse Gelsinger became the first person to die as an unintended consequence of gene replacement therapy research.9,10 Jesse had partial ornithine transcarbamylase (OTC) deficiency and received an infusion of a recombinant adenoviral vector that included the OTC gene. He experienced a severe immune reaction to the vector and died 4 days after receiving the injection.10

The recombinant adenoviral vector had not been considered to pose a risk.10 However, in a preclinical trial, a rhesus monkey died after an extremely high dose of a first-generation vector.11 Furthermore, Jesse, along with one other patient, received the highest dose of an adenoviral vector to be administered up to that point (3.8 × 1013 vector particles).11 At the time of Jesse’s death, over 4000 individuals had participated in approximately 400 gene therapy clinical trials, with no other deaths attributed to a gene delivery vehicle.9

Although this death caused setbacks for gene therapy research in the US, it led to the creation of new regulatory processes for gene therapy clinical trials.9,10

2003
China approved recombinant human p53 adenovirus* for clinical use (in vivo, adenoviral vector)

China approved recombinant human p53 adenovirus* for clinical use (in vivo, adenoviral vector)

In October 2003, China’s State Food and Drug Administration (SFDA) approved a gene therapy product (recombinant human p53 agent) for the treatment of head and neck squamous cell carcinoma (HNSCC).12–14 It can be delivered via numerous routes including intratumoral or intravenous injection, intrapleural and intraperitoneal infusion, intracavity or intravascular infusion, hepatic and lung artery infusion, and endotracheal and intravesical instillation.15

Recombinant human p53 is a replication-incompetent, recombinant, human adenovirus of serotype 5 designed to contain the human wild-type p53 tumor-suppressor gene. It is produced using a cell line that was subcloned from the human embryonic kidney (HEK) cell line 293.12

Over 12 years of commercial use of Gendicine in >30,000 patients, and >30 published clinical studies, it has demonstrated a favorable efficacy and safety profile in HNSCC and other cancer types.13

2008
First adenovirus-based gene therapy, sitimagene ceradenovec†, to complete a Phase 3 clinical trial

First adenovirus-based gene therapy, sitimagene ceradenovec†, to complete a Phase 3 clinical trial

In 2008, sitimagene ceradenovec became the first gene therapy product using an adenoviral vector that completed a Phase 3 clinical trial in Europe.5,16 However, in March 2010, Ark Therapeutics Group Ltd withdrew its application for marketing authorization following results that failed to confirm its therapeutic benefits in relation to risk.16,17

Sitimagene ceradenovec is an adenoviral vector harboring the gene for the herpes simplex virus thymidine kinase (HSV-tk), which was intended for the treatment of malignant brain tumors.5

2012
First gene therapy approved in the EU, alipogene tiparvovec‡, for the treatment of patients with familial LPLD (in vivo, AAV vector)

First gene therapy approved in the EU, alipogene tiparvovec‡, for the treatment of patients with familial LPLD (in vivo, AAV vector)

On October 25, 2012, the European Commission approved alipogene tiparvovec for the treatment of adult patients with lipoprotein lipase deficiency (LPLD) and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions.18,19 The indication was restricted to patients with detectable levels of lipoprotein lipase (LPL) protein18. LPLD is a rare genetic disorder caused by deficiency of LPL, which can cause severe pancreatitis, despite dietary fat restrictions.20

Alipogene tiparvovec, an adeno-associated virus serotype 1 (AAV1)-based vector engineered to express LPL in the muscle tissue21, became the first AAV gene therapy product approved in Europe19

In October 2017, alipogene tiparvovec was withdrawn from the market due to extremely limited usage.22 The withdrawal was not related to any risk–benefit concerns.22 Reasons cited for the withdrawal include the high manufacturing costs, extensive maintenance activities associated with its marketing authorization, a reduction of only 50% in the development of pancreatic disease, and approval in a very small patient population.22,23

2015
First oncolytic gene therapy, talimogene laherparepvec, approved in both the US and EU for early-stage metastatic melanoma

First oncolytic gene therapy, talimogene laherparepvec, approved in both the US and EU for early-stage metastatic melanoma

On October 27, 2015, the FDA approved talimogene laherparepvec for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery.50,51

On December 16, 2015, talimogene laherparepvec received approval by the European Commission for the treatment of adults with unresectable melanoma that is regionally or distally metastatic (stage IIIB, IIIC, and IVM1a) with no bone, brain, lung, or other visceral disease.52,53

Talimogene laherparepvec is a genetically modified HSV type 1 virus derived by functional deletion of two genes, ICP34.5 and ICP47, and insertion of the coding sequence for human GM-CSF. It is designed to replicate within tumors and produce the immune stimulatory GM-CSF protein. It causes lysis of tumors that is followed by release of tumor-derived antigens. These antigens, together with virally derived GM-CSF, may promote an antitumor immune response.50–53

2016
First ex vivo gene therapy, autologous CD34+ cells encoding the human ADA cDNA sequence*, approved (retroviral vector)

First ex vivo gene therapy, autologous CD34+ cells encoding the human ADA cDNA sequence*, approved (retroviral vector)

On May 26, 2016, the first ex vivo gene therapy, autologous CD34+ cells encoding the human ADA cDNA sequence, was approved by the European Commission for the treatment of severe combined immunodeficiency due to ADA deficiency (ADA-SCID), in patients who cannot be treated by a bone marrow transplant because they do not have a suitable, matched, related donor.24,25 Children born with ADA-SCID do not have a healthy, fully functioning immune system and as a consequence, are unable to fight off everyday infections.24,25

The therapy is an autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence.26 It replaces defective ADA in immune cells.27

*Brand name: Strimvelis®.

2017
First CAR T-cell therapy, tisagenlecleucel¶, approved by the FDA for B-cell ALL (ex vivo, lentiviral vector)

First CAR T-cell therapy, tisagenlecleucel¶, approved by the FDA for B-cell ALL (ex vivo, lentiviral vector)

On August 30, 2017, the FDA approved the first lentivirally transduced ex vivo gene therapy product tisagenlecleucel for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.28,29

Tisagenlecleucel is the first chimeric antigen receptor (CAR) T-cell immunotherapy approved by the FDA.28 It consists of autologous T cells collected in a leukapheresis procedure that are genetically modified with a new gene containing a CAR protein allowing the T cells to identify and eliminate CD19-expressing normal and malignant cells.28

2017
FDA approved axicabtagene ciloleucel# (ex vivo, retroviral vector)

FDA approved axicabtagene ciloleucel# (ex vivo, retroviral vector)

On October 18, 2017, the FDA approved the ex vivo gene therapy product axicabtagene ciloleucel for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.30,31

Axicabtagene ciloleucel is a chimeric antigen receptor (CAR) T-cell immunotherapy.30 It consists of autologous T cells that are genetically modified ex vivo by retroviral transduction to produce a CAR protein, allowing the T cells to identify and eliminate CD19-expressing normal and malignant cells.30,31

2017
First rAAV product approved in the US, voretigene neparvovec-rzyl** (in vivo)

First rAAV product approved in the US, voretigene neparvovec-rzyl** (in vivo)

On December 18, 2017, the FDA approved voretigene neparvovec-rzyl, the first gene therapy product for the treatment of children and adult patients with confirmed bi-allelic retinal pigment epithelium-specific 65 kDa protein (RPE65) gene mutation-associated retinal dystrophy32,33 that leads to vision loss and may cause complete blindness in certain patients.33

Voretigene neparvovec-rzyl is the first gene therapy product licensed in the US that targets a disease caused by mutations in a specific gene.33,34

Voretigene neparvovec-rzyl is an AAV2 that has been genetically modified to express the human RPE65 gene, which it delivers to retinal cells. These retinal cells then produce the normal RPE65 protein that converts light into an electrical signal, thus providing the potential to restore patient’s vision.32,33

2018
FDA approved tisagenlecleucel for DLBCL

FDA approved tisagenlecleucel for DLBCL

On May 1, 2018, the FDA approved the ex vivo gene therapy product tisagenlecleucel for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.29,35

2018
Ex vivo gene therapy products tisagenlecleucel and axicabtagene ciloleucel approved in the EU

Ex vivo gene therapy products tisagenlecleucel and axicabtagene ciloleucel approved in the EU

In August 2018, the European Commission granted approval for the two chimeric antigen receptor (CAR) T-cell therapies – tisagenlecleucel and axicabtagene ciloleucel.36,37

Tisagenlecleucel is approved for use in pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse. It is also approved to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.29

Axicabtagene ciloleucel is approved for adults with relapsed/refractory DLBCL and primary mediastinal large B-cell lymphoma after two or more lines of systemic therapy.38

2018
First gene therapy targeting a genetic disease approved in both the US and EU, voretigene neparvovec-rzyl

First gene therapy targeting a genetic disease approved in both the US and EU, voretigene neparvovec-rzyl

On November 22, 2018, the European Commission approved voretigene neparvovec, making it the first gene therapy targeting a genetic disease to receive approval in both the US and EU.39–40

This approval followed the issuance of a positive opinion recommending approval of voretigene neparvovec from the Committee for Medicinal Products for Human Use (CHMP) in September 2018.41

2019
First gene therapy approved in the US for the treatment of SMA, onasemnogene abeparvovec-xioi (in vivo, AAV vector)

First gene therapy approved in the US for the treatment of SMA, onasemnogene abeparvovec-xioi (in vivo, AAV vector)

On May 24, 2019, the FDA approved the first gene therapy for the treatment of spinal muscular atrophy (SMA), onasemnogene abeparvovec-xioi, which is a recombinant, self-complementary adeno-associated virus serotype 9 (AAV9) containing a transgene encoding the human survival motor neuron (SMN) protein.42,43

Patients can be treated with this therapy if they are younger than 2 years of age and have SMA characterized by bi-allelic mutations in the SMN1 gene.42,44

2019
First gene therapy approved for the treatment of transfusion-dependent β-thalassemia, autologous CD34+ cells encoding βA-T87Q-globin gene††

First gene therapy approved for the treatment of transfusion-dependent β-thalassemia, autologous CD34+ cells encoding βA-T87Q-globin gene††

On May 29, 2019, the European Commission approved the first gene therapy for the treatment of transfusion-dependent β-thalassemia, autologous CD34+ cells encoding βA-T87Q-globin gene.45,46 The βA-T87Q-globin gene is delivered to cells using a lentiviral vector.46,47

The therapy is indicated for patients who are at least 12 years of age with transfusion-dependent β-thalassemia who do not have a β0/β0 genotype, and for whom hematopoietic stem cell (HSC) transplantation is appropriate but a human leukocyte antigen-matched, related HSC donor is not available.47

2020
Onasemnogene abeparvovec approved in the EU for the treatment of SMA

Onasemnogene abeparvovec approved in the EU for the treatment of SMA

This approval makes onasemnogene abeparvovec the only gene therapy available in the EU for the treatment of SMA.48

Onasemnogene abeparvovec is indicated for the treatment of patients with 5q SMA with a biallelic mutation in the SMN1 gene and a clinical diagnosis of SMA Type 1, or patients with 5q SMA with a biallelic mutation in the SMN1 gene and up to three copies of the SMN2 gene.49

It delivers a fully functioning copy of the human SMN1 gene to promote the survival and function of motor neurons.48,49

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