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Gene Therapy: An Overview of Approved and Pipeline Technologies

March 2018

Summary

  • Gene therapy is an area of therapeutics aimed at curing, or significantly improving the management of, diseases with few or no treatment alternatives.
  • A large proportion of the candidates for gene therapy include advanced-stage cancer or hematological conditions. In addition, rare or inherited disorders are also frequent targets of gene therapy.
  • While gene therapy developments are still largely in the research stage, companies are increasingly investing in these technologies. Recently, a number of products have been approved outside of Canada or are in the advanced stage of clinical research.
  • The upfront current cost of gene therapy is generally very high. Multi-stakeholder dialogues around management of cost and reimbursement of these products are necessary.
  • Specialized manufacturing facilities, care centres, and clinicians trained to conduct customized procedures for such therapies are vital to ensure accessibility and quality of care.

Scope

This bulletin summarizes information on gene therapies that have been marketed in at least one country or are currently at an advanced or priority stage of development and are therefore most likely to appear on the market in the next two to three years. General aspects of adoption and implementation are considered, but clinical and cost-effectiveness of individual therapies are not reviewed. Details on mechanisms, processes related to manufacturing and administration, and regulatory aspects are not within the scope of this bulletin.

A comprehensive list of ongoing clinical trials on gene therapy around the world or in Canada is also not within the scope of this bulletin. This information may be found at ClinicalTrials.gov, maintained by the US National Library of Medicine,1 and Health Canada’s Clinical Trials Database.2

Methods

These bulletins are not systematic reviews of the literature and do not involve a detailed critical appraisal of identified studies. They are not intended to provide recommendations for or against a particular technology.

A limited literature search was conducted on key resources, including PubMed, the Cochrane Library, University of York Centre for Reviews and Dissemination databases, and Canadian and major international health technology agencies. As well, a focused Internet search was conducted. Methodological filters were applied to limit retrieval to randomized controlled trials, controlled clinical trials, and clinical studies. Where possible, retrieval was limited to the human population. The search was also limited to English-language documents published between January 1, 2016, and December 8, 2017. Regular alerts updated the search until project completion; only citations retrieved before January 30, 2018, were incorporated into the report.

Study Selection

The search results were divided between two authors by topic area. No duplicate screening was completed. In addition to the studies identified by the literature search, publications of interest cited by identified sources were also included in the report. As the report was intended to focus on the therapies most likely to appear on the market in the next two to three years, journal articles, database entries, or Web pages were considered for inclusion if they provided information on a gene therapy that has been approved for marketing anywhere in the world or was in active development, either in phase III or in earlier phases with a special regulatory designation. All indications were eligible.

Stakeholder Review

A draft version of this bulletin was posted publicly for stakeholder review.

Figure 1: Schematic of Approaches to Gene Therapy Applicable to Both Gene Editing and Gene Transfer

Figure from Shim et al., 201710 Source: Reproduced from Shim G, Kim D, Park GT, Jin H, Suh SK, Oh YK. Therapeutic gene editing: delivery and regulatory perspectives. Acta Pharmacol Sin. 2017 Jun;38(6):738-753. doi: 10.1038/aps.2017.2. Epub 2017 Apr 10. under Creative Commons licence (CC BY-NC-ND 3.0) https://creativecommons.org/licenses/by-nc-nd/3.0/

Background

What Is Gene Therapy?

According to the FDA, gene therapy is “the administration of genetic material to modify or manipulate the expression of a gene product or to alter the biological properties of living cells for therapeutic use.”3 In Canada, gene therapies are included in the definition of “drug” under the Food and Drugs Act and are regulated under the Food and Drug Regulations.4-6 Both the US and Canada regulate gene therapies as biologic drug therapies.3-5,7 Other jurisdictions, such as Europe, have a separate regulatory pathway for gene therapies.7,8

Gene therapy involves the administration of specific genetic material (i.e., DNA or RNA) via a carrier, known as a “vector,” that enables the foreign genetic material to enter the target cells.9 Most gene therapies use modified versions of natural viruses as vectors, as they are an efficient way of introducing DNA or RNA into a cell.8-10 The gene therapy agent can be injected into the body (in vivo gene therapy) or used to modify cells taken from the body, which are then re-infused (ex vivo gene therapy; Figure 1). Replacement gene therapy aims to provide a working copy of the damaged gene(s), boost the availability of a disease-modifying gene, or suppress the production of a damaged gene.8-10 Gene therapy for the treatment of cancer primarily aims to selectively kill, or suppress the growth of, malignant cells.11,12 Emerging “gene editing” technologies aim to modify chromosomal DNA and repair genetic errors directly.10

Gene therapy has been an active area of research for at least the past two decades.13 As of January 28, 2018, ten gene therapy products have been approved for marketing in at least one country in the world. Recent predictions for the near future range from 12 to 14 new gene therapies submitted for approval in the next couple of years,14 to around 40 new therapies approved by the end of 2022.15

This horizon scan focuses on the gene therapies that have been approved for marketing in one or more jurisdictions in the world or are in phase III of clinical development or phase I or II of clinical development with one or more special regulatory designations from the FDA or the European Medicines Agency (EMA). These designations are intended to accelerate development of drugs for underserved populations or unmet medical needs and are as follows:

  • Orphan Product (FDA)16
  • Fast Track (FDA)17
  • Breakthrough Therapy (FDA)18
  • Priority Review (FDA)19
  • RRare Pediatric Disease Priority Review (FDA)20
  • Orphan designation (EMA)21
  • PRIME (EMA)22
  • Priority Review (Health Canada)23
  • Notice of Compliance with Conditions (Health Canada).24

Further information concerning the regulatory context of gene therapy is reported in the concurrent CADTH Environmental Scan,25 while this horizon scan summarizes briefly the technologies, indications, status, and implementation issues surrounding gene therapies. CADTH has also produced a more comprehensive Horizon Scanning bulletin on voretigene neparvovec, a recently introduced gene therapy for an inherited retinal dystrophy.26

Who Might Benefit?

A 2017 brief by the Massachusetts Institute of Technology’s New Drug Development Paradigms Initiative (NEWDIGS) projected that around 40 gene therapies technologies would be approved by the end of 2022. The prediction is that 45% of these would be cancer treatments, 34% would be for the treatment of orphan diseases, 17% for common diseases, and 4% (one therapy) for extremely rare diseases (i.e., fewer than 100 patients within the US).15

The gene therapies that have made the most progress toward market availability treat disorders that are caused by single-gene mutations.9,10 Many of these are rare or ultra-rare diseases with few treatment options apart from supportive and symptomatic care. Development of gene therapies is also influenced by ease of administration in target tissues, e.g., diseases of the eye27 and of the hematopoietic system (immunity and blood).28,29

Until recently, progress in well-characterized single-gene conditions such as cystic fibrosis and the muscular dystrophies was slowed by the limitations of replacement gene strategies;30,31 gene editing approaches are now being investigated31 to address such shortcomings. Research groups and companies are also interested in replacement gene therapy for more prevalent acquired disorders, in which the production of certain proteins may have become insufficient,32,33 including cardiovascular and peripheral vascular disease; degenerative diseases of the nervous system (e.g., Parkinson disease, Huntington disease, and Alzheimer disease);34 and disorders of aging (such as osteoarthritis).

Cancers that have been targeted for gene therapy are primarily those that do not respond well to conventional treatment, such as metastatic melanoma, glioblastoma, cancer of the pancreas, and hepatocellular carcinoma.12 The first gene therapies to be approved in any country were approved in China for squamous cell carcinoma of the head and neck but have subsequently been used in other cancers.35 Hematopoietic cancers (lymphoma and leukemia) have also been the subject of investigation because of gene therapy’s ability to manipulate immune cells outside the body. Current gene therapy trials involve patients with relapsed or refractory disease whose treatment options are limited.11,12

Given the uncertainties around the use of novel therapies, gene therapies may initially be approved for patients who are lacking other treatment options. These include conditions that, in the absence of treatment, can cause disability or early death. Other patient groups that might benefit include those with conditions that require intensive and onerous maintenance therapy in the form of enzyme or protein replacement. Gene therapy could potentially offer all of these patients long-term stabilization or improvement of their health, with the ultimate objective being a cure. A review of the efficacy of these products is outside the scope of this review, but promising results have been obtained in several difficult-to-treat conditions.36-38

The Technologies

Vectors for Gene Transfer

Vectors used for gene therapy include modified versions of natural viruses and plasmids. Viruses have been modified to remove disease-causing genes and replace them with the gene(s) being transferred and the sequences that control its expression, while keeping the viral envelope or coat, which aids transfer.9,39 Plasmids are small circular segments of DNA that do not have a natural coat or envelope, but that can be encapsulated in an artificial lipid membrane or polymer to improve transfer.

Commonly used DNA viruses are adeno-associated virus (AAV) (a nonpathogenic but abundant small virus), adenoviruses (responsible for upper respiratory infections), and herpesviruses. RNA viruses include retroviral vectors derived from lentiviruses (such as human HIV-1) and gamma-retroviruses, all of which can integrate a DNA copy of their genetic material into the host genome.39

Choice of vector depends on the size of the gene or genes that it can carry, the target cells (dividing or nondividing, and cell type), whether the virus will insert into the target cells’ genome or remain separate, and the antibody status of potential patients. Insertion into the genome gives the most durable expression because the gene is retained after cell division. However, control over the location of insertion is essential, since insertion in the wrong place may lead to lack of expression of the inserted gene (if the gene inserts into a silenced part of the genome), or tumours arising from the disruption or activation of neighbouring genes involved in the development of cancer.40 Antigenic potential is important because many of the vectors are derived from native viruses; antibodies from a previous exposure to the native virus or to a therapeutic form can attack and destroy the administered vector or cells carrying it.41,9 Table 1 summarizes important properties of some common vectors.9,39

In Vivo Gene Therapy

In vivo gene therapy involves direct injection of the gene therapy agent into the body. Depending upon the vector and the target, in vivo gene therapy can be administered intravenously, injected into the muscles, infused or injected into an organ or bodily structure, or injected directly into a tumour.39

Table 1: Virus-Derived Vectors Commonly Used for Gene Therapy

  Adeno-Associated Virus Adenovirus Retrovirus/Lentivirus Herpesvirus
Genome ssDNA dsDNA ssRNA dsDNA
Allowable size of foreign
DNA
~5 kb 7.5 kb 8 kb > 25 kb
Type of cells targeted Nondividing cells Nondividing cells Dividing and
nondividing cells
Dividing and
nondividing cells
Integration into genome No No Yes No
Duration of expression Potentially long duration Transient Long duration Potentially long
duration
Immunogenicity Presence of antibodies
varies by serotype
Antibodies prevalent Used ex vivo Antibodies prevalent

Ex Vivo Gene Therapy

In an ex vivo delivery system, cells are harvested from the patients’ own body (autologous) or other healthy individuals (allogeneic or donor).10 They are then modified using genetic engineering tools outside the body and purified, enriched, and/ or activated before being transplanted back into the patient.10 These modified cells then further replicate and spread in the body. The ex vivo strategy allows the transfer of a gene or genes to a specific cell subpopulation without affecting other cells or organs; however, the vectors used must be able to integrate the genetic material in the genome for successful long-term clinical effect.10 Most ex vivo therapies are based on cells from autologous sources, with a few exceptions.10 Autologous cells are less likely to be the targets of immune reactions than allogeneic cells. However, the latter have fewer supply and manufacturing issues, thus making them ideal candidates for off-the-shelf products, although their propensity for immune rejection or reaction against the recipient’s tissues still poses technical challenges.10

Gene Editing

In this approach, gene editing machinery is directly transferred into host cells (using either ex vivo or in vivo approaches) to modify the genome within the recipient rather than using vectors to transfer the modified genes. Unlike viral vectors, which may have a transient effect and supplement missing or defective genes, gene editing technologies can be used to add, inactivate, or correct a gene with a permanent effect.10

Gene editing is carried out using nucleases, enzymes that bind to DNA with varying degrees of specificity and produce breaks on both strands. The breaks are then fused together (foreign gene from another source) using the genetic template supplied, resulting in the insertion, deletion, or correction of a gene. The three major types of nucleases used for gene editing are:10

  • zinc finger nuclease (ZFN)
  • transcription activator-like effector nuclease (TALEN)
  • clustered regularly interspaced short palindromic repeats–associated nuclease Cas9 (CRISPR/Cas9).

Genome editing technologies vary in their complexity of design, manufacturing process, activity, and specificity. For example, ZFN- and TALEN-based technologies are difficult to engineer, time-consuming, and expensive, limiting their clinical application.10 CRISPR/Cas9-based technologies have design features that make them better suited to gene editing in ex vivo settings and have recently seen a surge in clinical applications. However, no individual gene editing therapy was sufficiently advanced in development to be addressed in this report.10

Chimeric Antigen Receptor T-Cell Therapy

Chimeric antigen receptor (CAR) T-cells are a relatively recent development in the area of gene therapy, which have shown significant potential in recent years and therefore warrant a separate discussion. These are T-cells genetically engineered to express receptors to recognize antigens that are commonly expressed on tumour cells. Upon recognizing tumour-specific antigens, CAR T-cells are activated, leading to an increase in their numbers and to the secretion of immune activators, which work towards the targeting and destruction of tumours.9 To date, various tumour antigens (e.g., CD19, B cell maturation antigen [BCMA]) and vector or editing systems (e.g., lentiviral vectors, transposons, mRNA, CRISPR/Cas9) have been investigated in the CAR T-cell approach. CAR T-cells combine the ability of monoclonal antibodies (mAbs) to identify specific targets and the ability of T-cells to activate the immune system and kill target cells.9

The general approach for CAR T-cell therapy is similar to ex vivo methods for cell-based therapies (Figure 1). First, cells from patients are collected by leukapheresis in the primary care centre, and then specific T-cells are isolated, enriched, and activated in the manufacturing facility. Next, viral vectors are used to transfer CAR genes into T-cells, and the cells are grown before being transferred back to the hospital to be infused into the patient. Patients are conditioned with lymphodepleting chemotherapy before CAR T-cell infusion in order to minimize host immune reaction and to enhance T-cell growth and antitumour activity. CAR T-cells, therefore, have significant overlap with cell-based therapies in their manufacturing and administration process, while having the distinct property of acquiring new function through the introduction of new genetic material, albeit exogenously, without altering host DNA.9

Current research is aimed at expanding the CAR T-cell approach to myeloid malignancies and solid tumours. However, due to the lack of confirmed tumour-specific cell surface antigens and delivery method into solid tumours or immune-privileged sites, CAR T-cell treatment has yet to be successfully used in solid tumours. Research is also under way to develop allogeneic CAR T-cell therapies that can be used “off the shelf” without invoking rejection or graft-versus-host disease. Success in treatment of certain cancers has led to T-cell–based therapies for other diseases, such as autoimmune disorders and AIDS9 (Table 2).

Table 2: Summary of the Development and Regulatory Status of Gene Therapies Described in this Bulletin

Therapies are organized by virus and method of administration (in vivo or ex vivo).

Name Manufacturer Indication Administration Phase Orphan Drug FDA Fast Track FDA Breakthrough FDA Priority FDA Orphan Drug EMA PRIME EMA Priority EMA Accelerated Assessment
AAV
Voretigene neparvovec-rzyl Spark Vision loss
due to RPE65
mutations
In vivo M Y     Y     Y  
Valoctocogene roxaparvovec BioMarin Hemophilia A In vivo III Y   Y     Y Y  
GS010 Gensight LHON In vivo III Y       Y      
AVXS-101 AveXis SMA Type 1 In vivo IIIa Y Y Y   Y      
AMT-061 uniQure Hemophilia B In vivo IIIa Y   Y     Y    
NSR-REP1 Nightstar
Therapeutics
Chloroideremia In vivo IIIa Y              
Mydicar Theragene Heart failure In vivo IIIa     Y          
SPK-9001 Spark/Pfizer Hemophilia B In vivo II Y   Y     Y    
ABO-102 Abeona MPS IIIA In vivo II Y Y     Y      
AAV1-Follistatin Milo Becker MD In vivo II Y              
Adenovirus
Gencidine Shenzen Sibiono
GeneTech
Head and neck
cancer
In vivo M                
Oncorine Shanghai Sunway Head, neck,
esophagus
In vivo M                
Alferminogene tadenovec Gene
Biotherapeutics
Angina In vivo IIIa   Y            
RT-100 Renova Heart failure In vivo IIIa   Y            
DNX-2401 DNAtrix Glioblastoma /
gliosarcoma
In vivo II Y              
ONCOS-102 Targovax Mesothelioma In vivo I/II         Y      
Ofranergene obadenovec
(VB-111)
VBL Therapeutics Glioblastoma In vivo III Y Y     Y      
Herpervirus
Talimogene/ Iaherparepvec BioVec/Amgen Melanoma In vivo M                
Sepravir Virtuu Mesothelioma In vivo I/II                
Vaccinia
Pexastimogene
devacirepvec (Pexa-Vec)
SillaJen Hepatocellular
carcinoma
In vivo III                
Plasmid
Neovasculgen Human Stem Cells
Institute
Critical limb
ischemia
In vivo M                
Beperminogene perplasmid
(Collategene, AMG0001,
HGF plasmid)
Mitsubishi Tanabe
Pharma
Critical limb
ischemia
In vivo IIIa                
VM202 ViroMed Diabetic
foot ulcers,
neuropathy
In vivo III                
CAR T-cell
Tisagenlecleucel (Kymriah) Novartis Relapsed or
refractory B cell
ALL Relapsed
or refractory
DLBCL
Ex
vivo
M       Y       Y
Axicabtagene ciloleucel
(Yescarta)
Gilead Sciences Relapsed or
refractory BCL
Ex
vivo
M Y   Y Y   Y    
Lisocabtagene maraleucel
(JCAR017)
Juno
Therapeutics,
Celgene
Relapsed or
refractory
DLBCL
Ex
vivo
I     Y     Y    
bb2121 Bluebird Bio,
Celgene
Relapsed or
refractory MM
Ex
vivo
I, II     Y     Y    
Lentivirus
LentiGlobin
(LentiGlobin BB305)
Bluebird Bio Betathalassemia, SCD Ex
vivo
I, II,
III
    Y   Y Y   Y
Elivaldogene tavalentivec
(Lenti-D)
Bluebird Bio CALD Ex
vivo
II/III                
GSK2696274 GSK MLD Ex
vivo
III                
OTL-101b Orchard
Therapeutics
ADA-SCID Ex
vivo
I/II Y   Y         Y
G1XCGD Genethon X-CGD, WAS Ex
vivo
I/II         Y      
Retrovirus
Strimvelis GSK ADA-SCID Ex
vivo
Mc Y       Y      
Nalotimagene carmaleucel
(Zalmoxis)
MolMed SpA Blood cancers Ex
vivo
Mc,
III
        Y      
Tonogenchoncel-L (Invossa/
TG-C)
TissueGene Inc. OA Ex
vivo
M,
IIIa
               
Vocimagene amiretrorepvec
(Toca 511)
Tocagen Glioma Ex
vivo
III     Y     Y    
NY-ESO-1(c259) T-cells Adaptimmune,
GSK
SS, MM Ex
vivo
I/II     Y     Y    

ALL = acute lymphocytic/lymphoblastic leukemia; AAV = adeno-associated virus; ADA-SCID = adenosine deaminase severe combined immunodeficiency;
BCL = B cell lymphoma; CAR T = chimeric antigen receptor T-cells; CALD = cerebral adrenoleukodystrophy; DLBCL = diffuse large B cell lymphoma;
HSV = herpes simplex virus; LHON = Leber hereditary optical neuropathy; MD = muscular dystrophy; MLD = metachromatic leukodystrophy; MM = multiple myeloma;
MPS IIIA = Sanfilippo syndrome type A; OA = osteoarthritis; Plas = plasmid; SCD = sickle cell disease; SMA = spinal muscular atrophy; SS = synovial sarcoma;
WAS = Wiskott-Aldrich syndrome; X-CGD = X-linked chronic granulomatous disease; Y = yes.
Note: Trials in phase are ongoing unless otherwise indicated.
a Initiating trials.
b OTL-101 has received a Rare Pediatric Disease Designation.
c Conditional Market Authorization in EU.

Regulatory and Development Status

Approved Gene Therapies

North America

Canada

No gene therapies have been approved in Canada as of January 30, 2018.

US

Two ex vivo and two in vivo gene therapies have received marketing approval in the US. All four use gene transfer technologies rather than gene editing; no gene editing technologies have been approved in the US.

The approved therapies are listed below in order of date of approval. Special regulatory designations are presented in Table 2.

  • Talimogene laherparepvec (Imlygic, BioVec, a subsidiary of Amgen) was granted conditional approval by the FDA in October 2015 for the treatment of patients with subcutaneous or lymph node melanoma that cannot be surgically removed.42 It consists of recombinant herpesvirus that contains specific deletions that allow the virus to replicate and lyse tumour cells, as well as a gene carrying granulocyte-macrophage colony-stimulating factor (GMCSF), intended to stimulate a systemic immune response against the remaining tumour and metastases. It is administered by intratumoural injection. 43
  • Tisagenlecleucel (Kymriah, Novartis Pharmaceuticals Corporation) is a cancer treatment approved in the US for patients up to 25 years old who have acute lymphoblastic leukemia (ALL) that is either relapsed (returned postremission) or refractory (did not go into remission following other leukemia treatments). It is the first CAR T-cell therapy approved by the FDA (August 2017).44 It consists of autologous T-cells genetically modified using a lentiviral vector to encode an anti-CD19 CAR. Tisagenlecleucel has been submitted for approval to the EMA for relapsed or refractory B cell ALL in children or young adults45 and submitted to the FDA and EMA for a second indication, relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in adults,45,46 for patients who are ineligible for autohematopoietic stem cell transplantation (HSCT).45
  • Axicabtagene ciloleucel (Yescarta, Kite, a subsidiary of Gilead Sciences, Inc.47) was approved by the FDA in October 2017 for the treatment of adult patients with relapsed or refractory large B cell lymphoma after two or more lines of systemic therapy, including patients with DLBCL not otherwise specified, primary mediastinal large B cell lymphoma, high-grade B cell lymphoma, and DLBCL arising from follicular lymphoma.48 It is a CD19-directed autologous T-cell immunotherapy genetically modified using a retroviral vector. An application for European marketing authorization has been submitted to the EMA.49
  • Voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics) was granted approval by the FDA in December 201750 for the treatment of patients with progressive vision loss due to a confirmed biallelic (affecting both copies) mutation in the RPE65 gene.51 Voretigene neparvovec-rzyl consists of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a functional RPE65 gene, with the aim of supplying a functional RPE65 protein. It is given by bilateral subretinal injection.52 An application for European marketing authorization has been submitted.53 In addition, CADTH has published a Horizon Scanning bulletin on voretigene neparvovec, including an overview of the evidence of its efficacy and safety.26

Other Countries

An additional seven gene therapies have received marketing authorization elsewhere in the world. All approved gene therapies use gene transfer technologies. Therapies with approval in the European Union (EU) and other jurisdictions are as follows, in the order of their approval date.

  • Gencidine (Shenzhen Sibiono GeneTech) was approved by the Chinese State Food and Drug Agency in 2003 for the treatment of squamous cell carcinoma of the head and neck.35 Gencidine is a recombinant adenovirus engineered to express wildtype p53, a tumour suppressor protein, intended to induce programmed cell death in tumour cells. It is administered by intratumoural injection.
  • Oncorine (H101, Shanghai Sunway Biotech) was approved by the Chinese State Food and Drug Agency in 2005 for the treatment of squamous cell carcinoma of the head, neck, and esophagus.35 Oncorine is a recombinant adenovirus engineered to selectively replicate in and destroy tumour cells and is administered by direct intratumoural injection.
  • Neovasculgen (PI-VEGF-165, Human Stem Cells Institute) was approved by the Russian Ministry of Healthcare in 2011 for the treatment of peripheral vascular disease with critical limb ischemia. Neovasculgen is a plasmid-carrying vascular endothelial growth factor that induces the growth of new vessels.
  • Talimogene laherparepvec (Imlygic, BioVec, a subsidiary of Amgen) was approved in the EU in December 2015 for the treatment of adults with unresectable melanoma that is regionally or distantly metastatic (Stage IIIB, IIIC, and IVM1a) with no bone, brain, lung, or other visceral disease.43
  • Strimvelis (GlaxoSmithKline) was approved in the EU in May 2016 but saw the first clinical application on a single patient in March 2017. This therapy is targeted for the treatment of a rare genetic disorder, adenosine deaminase deficiency– severe combined immunodeficiency (ADA-SCID) in patients for whom no suitable, matched stem cell donor is available.54 It uses autologous CD34+ enriched cells transduced with retroviruses to encode the human adenosine deaminase (ADA) gene. The genetically modified autologous CD34+ cells act by repopulating the hematopoietic system with cells that express active levels of the ADA enzyme, reversing the enzyme deficiency.55,56 This therapy was given orphan medication designation by the EMA.55,56
  • Nalotimagene carmaleucel (Zalmoxis, MolMed SpA) was granted a conditional marketing authorization (CMA) by EMA on August 2016 and was designated an orphan medicinal product. The CMA authorization indicates that an unmet need is filled by the treatment.57 A phase III trial is underway around the world for this treatment.58 Nalotimagene carmaleucel consists of allogeneic T-cells genetically modified with a retroviral vector encoding for the human lowaffinity nerve growth factor receptor and the herpes simplex I virus thymidine kinase. It is recommended as an adjunct treatment for adult patients who have undergone HSCT.57,59
  • Tonogenchoncel-L (TG-C, Invossa, TissueGene) received marketing approval from the Korea Ministry of Food and Drug Safety in July 2017. In the US, a phase III trial is ongoing.60 This is an allogeneic cell therapy in which a mix of unmodified and genetically modified chondrocytes made to express transforming growth factor beta-1 (TGF-beta-1), and anti-inflammatory mediator are injected.61

In addition, alipogene tiparvovec (Glybera, uniQure) was awarded a five-year marketing authorization in the EU in October 2012 for the treatment of monogenic lipoprotein lipase deficiency, an ultra-rare inherited disease.62 One patient received treatment, post-marketing. The company decided not to reapply for marketing authorization for October 2017.63

Gene Therapies in Advanced Development

Fourteen gene therapies are in advanced development, either with (1) current phase III trials or with (2) completed phase II or phase I/II trials with one or more special regulatory designations and plans to initiate phase III trials in 2018. Eleven involve in vivo administration of viruses or plasmids, and three involve ex vivo manipulation and infusion of autologous cells. Special regulatory designations are presented in Table 2.

  • GS010 (Gensight Biologics) for the treatment of patients with vision loss from Leber hereditary optical neuropathy involving the ND4 gene — a subunit of an important enzyme of the mitochondrial energy pathway.64 GS010 consists of an AAV9 vector carrying a functional copy of ND4, administered by intravitreal injection.65,66
  • NSR-REP1 (Nightstar Therapeutics) for the treatment of patients with vision loss due to choroideremia.27,67 NSRREP1 consists of an AAV2 vector carrying human REP1 administered by intraretinal injection.
  • Valoctocogene roxaparvovec (BioMarin Pharmaceuticals) for the treatment of patients with hemophilia A.68 Valoctocogene roxaparvovec consists of an AAV vector carrying a functional coagulation factor VIII gene, administered by intravenous infusion.69,70
  • AMT-061 (uniQure) for the treatment of patients with hereditary hemophilia B.68 AMT-061 consists of an AAV5 vector carrying a functional gene for coagulation factor XI administered by intravenous infusion.71
  • AVXS-101 (AveXis) for the treatment of children with spinal muscular atrophy (SMA) Type I.72 AVXS-101 consists of a recombinant AAV9 virus carrying a functional copy of the SMN1 gene, administered by intravenous injection.56
  • Alferminogene tadenovec (Generx, Gene Biotherapeutics [formerly Taxus Cardium Pharmaceuticals Corporation]73) is entering phase III development for the treatment of patients with angina pectoris due to cardiac insufficiency in association with advanced coronary disease.74 Alferminogene tadenovec consists of an adenoviral (Ad5) vector carrying fibroblast growth factor 5, administered by intracoronary injection. It is intended to improve collateral circulation in the heart by promoting angiogenesis in patients whose symptoms could not be relieved by conventional treatment of coronary artery disease.
  • RT-100 (Renova Therapeutics75) is entering phase III development for the treatment of patients with reduced left ventricular ejection fraction heart failure.76 RT-100 consists of an Ad5 vector carrying human adenylyl cyclase 6 administered by intracoronary injection. It is intended to improve the contractility of the heart muscle in patients with heart failure that has not responded to best current care.
  • RT-100 (Renova Therapeutics75) is entering phase III development for the treatment of patients with reduced left ventricular ejection fraction heart failure.76 RT-100 consists of an Ad5 vector carrying human adenylyl cyclase 6 administered by intracoronary injection. It is intended to improve the contractility of the heart muscle in patients with heart failure that has not responded to best current care.
  • Pexastimogene devacirepvec (Pexa-Vec, SillaJen, Inc.80) is currently in phase III development 81 for the treatment of hepatocellular carcinoma in conjunction with immunotherapy. Pexastimogene devacirepvec is a recombinant oncolytic vaccinia virus administered by injection directly into the tumour or tumours.
  • Beperminogene perplasmid (Collategene, AMG0001, hepatocyte growth factor (HGF) plasmid; AnGes MG / Mitsubishi Tanabe Pharma) for the treatment of peripheral vascular disease with critical limb ischemia. It consists of a plasmid containing human HGF gene. A phase III study has been completed in Japan. A separate phase III multi-national study was terminated in 2016,82 with plans to revise the scope and re-initiate.
  • VM202 (VM Biopharma) is being developed for the treatment of diabetic foot ulcers 83 and painful diabetic peripheral neuropathy.84 It is a plasmid containing human HGF gene. Phase II studies have been completed for critical limb ischemia.85
  • LentiGlobin (BB305, Bluebird Bio) consists of autologous CD34+ hematopoietic stem cells (HSCs) transduced ex vivo with a recombinant lentiviral vector that restores the function of the beta-globin gene that is defective in patients with beta-thalassemia.86 This is considered an orphan medication in the EU.86 Currently, this therapy is in a phase III trial for beta-thalassemia87 and a phase I trial for sickle cell disease.88,89
  • Elivaldogene tavalentivec (Lenti-D, Bluebird Bio) is another autologous CD34+ HSC product being tested on patients with cerebral adrenoleukodystrophy in a phase II/III study.90,91
  • GSK2696274 (GlaxoSmithKline) consists of cryopreserved autologous CD34+ cell clusters transduced with lentiviral vector to express arylsulfatase A and used for the treatment of metachromatic leukodystrophy, a lysosomal storage disorder characterized by severe and progressive demyelination affecting the central and peripheral nervous system. This therapy is currently being tested in a phase III trial.92

Gene Transfer Therapies in Earlier Development

A number of other gene therapies are in phase II or earlier development. Thirteen technologies that have received one or more forms of special regulatory designation intended to accelerate development are described in brief. Special regulatory designations are presented in Table 2.

  • SPK-9001 (Spark Therapeutics) is in phase I/II development for the treatment of patients with hereditary hemophilia B.68 SPK-9001 consists of an AAV vector carrying the gene for coagulation factor XI, administered by intravenous infusion.93
  • ABO-102 (Abeona Therapeutics, Inc.) is in development for the treatment of children with Sanfilippo syndrome type A (MPS IIIA, a lysosomal storage disorder).94,95 ABO- 102 consists of a recombinant AAV9 vector carrying the N-Sulfoglucosamine Sulfohydrolase gene, administered by intravenous infusion.
  • AAV1-Follistatin (Milo Biotechnology) is in development for the treatment of Becker muscular dystrophy.96 AAV1- Follistatin consists of a recombinant AAV1 vector carrying the follistatin gene. Treatment is by intravenous infusion.97
  • Mydicar (Theragene Pharmaceuticals) is for the treatment of heart failure. Mydicar consists of an AAV1 vector carrying sarcoplasmic reticulum calcium ATPase (SERCA2a, downregulated in heart failure), administered by intracoronary injection. The phase IIb clinical trial for Mydicar did not reach its primary end point,32,98 but the drug was acquired by Theragene Pharmaceuticals and is continuing in active development.
  • Lisocabtagene maraleucel (JCAR017, Juno Therapeutics, in collaboration with Calgene Corporation) is one of a range of CAR T-cell products developed by these companies. JCAR017 is an immunotherapy that targets CD19 receptors on malignant B cells. The therapy is currently being tested in patients with relapsed or refractory chronic lymphocytic lymphoma or small cell lymphocytic lymphoma (phase I/II)99 and relapsed or refractory B cell non-Hodgkin lymphoma.100
  • bb2121 (Bluebird Bio101 / Celgene) is in phase I/II development in patients with previous treatment for multiple myeloma.102,103 bb2121 consists of autologous T lymphocytes transduced with an anti-BCMA02 CAR lentiviral vector carrying an anti-BCMA CAR).
  • DNX-2401 (DNAtrix104) is in phase II development for glioblastoma or gliosarcoma with disease progression.105 DNX-2401 is a recombinant adenovirus and is administered by direct intratumoural injection.
  • ONCOS-102 (Targovax106) is in phase I/II development for malignant pleural mesothelioma.107 ONCOS-102 is a recombinant adenovirus expressing GM-CSF, intended to lyse tumour cells and stimulate an immune response to the remaining tumour and remote metastases. It is administered by injection into the pleural space in conjunction with intravenous chemotherapy.
  • Sepravir (Virtuu Biologics108) has completed phase I/II trials for treatment of malignant pleural mesothelioma.109 Sepravir is a recombinant oncolytic herpes simplex I virus administered intrapleurally in conjunction with intravenous chemotherapy.
  • Vocimagene amiretrorepvec (Toca 511, Tocagen110) is a cancer-selective immunotherapy consisting of a retroviral vector encoding a modified cytosine deaminase gene (Toca 511) that expresses cytosine deaminase, an enzyme that converts the orally administered antifungal prodrug 5-flurocytosine to the anticancer drug 5-fluorouracil in transfected cells.111,112 The treatment is tested in phase II/III clinical trial on patients with recurrent high-grade glioma.113
  • NY-ESO-1 (Adaptimmune, in collaboration with GlaxoSmithKline) is an autologous T-cell therapy transduced function of the beta-globin gene that is defective in patients with beta-thalassemia.86 This is considered an orphan medication in the EU.86 Currently, this therapy is in a phase III trial for beta-thalassemia87 and a phase I trial for sickle cell disease.88,89
  • OTL-101 (Orchard Therapeutics Limited) has received FDA Rare Pediatric Disease, Orphan Drug, and Breakthrough Therapy designations. It is an autologous CD34+ HSC treatment encoding for the ADA gene for use in ADA-SCID patients. Its safety and efficacy are being tested in a phase I/ II trial.116,117
  • G1XCGD (Genethon) involves autologous CD34+ cells transduced with lentiviral vectors to restore function of the Nicotinamide adenine dinucleotide phosphate oxidase enzyme for the treatment of X-linked chronic granulomatous disease, a rare genetic disorder affecting boys that weakens the immune system and makes the carrier prone to infection. Genethon is testing another lentivirus-mediated therapy for Wiskott-Aldrich syndrome (WAS),118 an inherited immune deficiency primarily affecting males that causes hemorrhaging and eczema as a result of a defective WAS gene and subsequent impaired blood clotting. Both of these therapies are currently in phase I/II trials.119, 120

Gene Editing Therapies in Early Development

As of 2017, there were 18 gene editing–based technologies being tested in clinical trials in at least one country in the world, most in phase I trials.

No clinical trials (ongoing or completed) using gene editing– based technologies have progressed beyond phase II. The few studies in phase I/II are as follows.

  • Sangamo Biosciences has completed a phase I/II trial of a ZFN-based product, SB-728-T, which is an autologous CD4+ T-cell therapy for silencing the CCR5 gene to combat HIV infection.121
  • CRISPR/Cas9-based technology is currently ongoing and in early stages of clinical trials in China. In one ongoing phase II trial, PD-1 (Programmed cell death protein 1) knockout T-cells created using CRISPR/Cas9 technology ex vivo are used to treat advanced esophageal cancer.122 CRISPR/Cas9- mediated PD-1 knockout Epstein-Barr virus (EBV)–specific cytotoxic T-cells are tested in phase I/II for treatment of a number of EBV-positive advanced stage malignancies — gastric carcinoma, nasopharyngeal carcinoma, lymphoma, Hodgkin lymphoma, and diffuse large B-cell lymphoma.123 Finally, allogeneic CAR T-cells, UCART019, engineered to target relapsed or refractory CD19+ leukemia and lymphoma, are being tested in a phase I/II trial.124

Costs

No gene therapies have been approved in Canada; therefore, Canadian list prices are unavailable.

US list prices are available for the following five gene therapies marketed in the US. A review of the cost-effectiveness and health system value of these technologies is out of scope for this report, but the Institute for Clinical and Economic Review has reviewed the cost-effectiveness of two CAR T-cell therapies.125

  • Voretigene neparvovec-rzyl (Luxturna) has a list price of US$425,000 (per eye treatment).126 Administration requires a bilateral subretinal injection in two separate procedures no less than six days apart.127 Subretinal injection requires vitrectomy to access the retina and is specialized eye surgery that will likely be available only in a limited number of centres. Travel costs, therefore, may be incurred.
  • Talimogene laherparepvec (Imlygic) has an estimated average cost of US$65,000 according to the manufacturer,128 but this may vary by patient. It is administered as a series of injections over at least six months, in conjunction with standard chemotherapy, until there are no remaining injectable lesions or other treatment is needed.42 Injections are subcutaneous or intranodal, so no surgical procedure costs are anticipated.
  • Tisagenlecleucel (Kymriah) has a list price of US$475,000, but estimates are up to US$750,000.129 It is administered by intravenous infusion, following lymphodepleting chemotherapy. There is no information on cost per dose. Additional costs are incurred pre-treatment and for the management of treatment side effects. Therefore, the total cost may surpass the estimated cost.130-132
  • Axicabtagene ciloleucel (Yescarta) has a list price of US$373,000.125,133-135 It is administered by intravenous infusion, preceded by lymphodepleting chemotherapy (fludarabine and cyclophosphamide). Additional costs are incurred pre-treatment and for the management of treatment side effects.
  • Strimvelis has a list price of €594,000.54 It is administered as a single dose through intravenous infusion.55,56 It is recommended that Strimvelis infusion be preceded by intravenously administered busulfan to eliminate abnormal bone marrow cells andantihistamine to reduce the risk of allergic reactions.55,56 Strimvelis should be administered in a specialized transplant centre, by a physician experienced with ex vivo cell therapy products and management of patients with ADA-SCID.

Concurrent Developments

Gene therapy is a very active area of research and development, in which existing technologies are being further developed for additional indications. For example, the same or a closely related vector is used to deliver different genes (e.g., for inherited retinal disease),27 and different gene therapies are being developed for the same conditions (e.g., multiple companies are developing treatments for hemophilia A or B).

Additional Indications for Existing Technologies

The following gene therapies are being investigated for additional indications. The primary indication is shown in brackets after the gene therapy name.

  • Voretigene neparvovec-rzyl (vision loss due to RPE65 gene mutations) is being developed for the treatment of patients with retinitis pigmentosa and has received breakthrough designation for this indication. It is also in pre-clinical development for wet age-related macular degeneration, a much more common condition.136
  • Neovasculgen is being investigated for Raynaud syndrome secondary to scleroderma, as well as diabetic foot ulcers, and peripheral nerve injury.137
  • AVXS-101 (SMA Type 1) is in phase II/III development for patients with SMA Type 2, who are able to sit unassisted but not walk. These patients have a nonfunctioning SMN1 gene but have extra copies of a similar gene, SMN2, that partially corrects the deficit.138
  • AAV-Follistatin is in phase I development for Duchenne muscular dystrophy139 and inclusion body myositis.139
  • Oncorine (head and neck cancer) is also used to treat lymph node metastases of these cancers, hepatocellular cancer, and pancreatic cancer.35,140
  • Pexastimogene devacirepvece is in phase II and earlier development for other cancers.80
  • Ofranergene obadenovec is in phase II development for thyroid cancer and lung cancer.77
  • DNX-2401 is also in phase I development for pediatric pontine glioma.141
  • ONCOS-102 is also in phase I development for melanoma and advanced peritoneal cancers.106
  • Beperminogene perplasmid is also being developed, in alliance with Mitsubishi Tanabe Pharma, for arteriosclerosis obliterans and Buerger’s disease.142
  • VM202 has completed phase I/II trials for amyotrophic lateral sclerosis and received a Fast Track designation for this indication, and is in development for coronary artery disease.143

Implementation Issues

Some of the main implementation issues for gene therapy involve the adequacy of evidence for decision-making, the cost of treatment, and health care system requirements that need to be in place (e.g. relevant procedures and aftercare).9,10

Adequacy of Evidence for Decision-Making

Because some gene therapy technologies are supported by regulators through accelerated review mechanisms, there is a risk that they will reach the market on the basis of early evidence (e.g., a small number of patients, use of surrogate end points, short duration of treatment or followup, lack of safety information), posing challenges for health technology assessment agencies and payers.144 In these cases, decision-makers may be required to determine eligibility for reimbursement on the basis of a small body of evidence, which may result in contradictory decisions neighbouring jurisdictions, or resistance to the withdrawal of a therapy even if later evidence does not support its effectiveness, particularly if there are no alternatives. Availability of ongoing research that provides effectiveness and safety data may help to overcome these limitations. Regulatory agencies may have mechanisms for ongoing review or reassessment that could be applied in these scenarios.

Areas of particular uncertainty concern the predictability and durability of the response to treatment and the long-term safety of gene therapies for patients, those in contact with them, and the environment. Most trials have observed a variable response among patients. The clinical response to gene therapy technologies does not always follow a pattern similar to conventional pharmaceutical or biologic drugs, and instead may demonstrate rapid turn-on or turn-off effects.10 To date, most studies of gene therapies involve relatively short follow-up for treatment intended to be long-term or permanent. The ability of these technologies to produce long-term or even permanent genome changes may also pose unique challenges related to safety.10 Gene therapy has been associated with unexpected adverse effects, such as leukemia in children successfully treated for severe inherited immunodeficiency.40 Safety concerns associated with gene therapies also vary by technology. Tisagenlecleucel and axicabtagene ciloleucel, for example, have been associated with a potentially lifethreatening side effect called cytokine release syndrome as well as serious neurologic changes and weakening of the immune system.132,134 There is at least a theoretical risk of transfer of viral vectors capable of gene editing to sexual partners, others, or the environment.5,10 Not all of these risks have been fully elucidated, and long-term data (covering the expected duration of effect) are not yet available. Ongoing research and development may support advancements in the effectiveness and safety of gene therapy, as it has over the past 20-plus years of gene therapy research.13,145

Cost of Therapy and Need for Reimbursement Across Jurisdictions

Gene therapies approved to date have been expensive, with costs ranging from US$65,000 to greater than US$1 million (alipogene tiparvovec). This reflects the initial investment in a new technology and the very small patient pool for the initial therapies. Costs for individual treatments are expected to decrease as additional therapies enter the market and more common diseases are targeted,146 although the potential budget impact of a gene therapy cure for highly prevalent diseases could be substantial. The budget impact of advanced therapy medicinal products for heart failure has been estimated at €348 billion147 and for Alzheimer disease, £72 billion.144,148 Most complex, multifactorial disorders are not, however, immediate targets for gene therapy.

It is critical to engage the organizations responsible for insurance and reimbursement, government regulatory bodies, and relevant stakeholders to develop models for reimbursement that account for one-time treatment with high upfront costs and potential long-term benefits that would offset a lifetime of medical costs.144 The likely need for gene therapies to be developed and administered at specialist centres further increases the challenges. Approval for treatment and reimbursement across boundaries (national, regional, district, between insurers/formularies) is complex, even for costs that are a fraction of the expected cost for gene therapy, and such cross-boundary treatment must involve negotiated agreements between the treating centre and multiple jurisdictions.29 Costs and challenges in reimbursement were cited as reasons that the manufacturer decided not to apply for renewal of the fiveyear European marketing authorization originally granted to alipogene tiparvovec.63

Procedural Requirements and Aftercare

Gene therapies often require specialized manufacturing facilities, care centres, and clinicians trained to conduct customized procedures for such therapies. Manufacturers are required to strictly follow FDA and EMA regulations to control consistency, purity, and sterility of the vectors for administration to cells or people, and the viability and number of gene-modified cells.10 Administration may require specialized surgical intervention; for instance, the administration of voretigene neparvovec requires removal of the posterior cortical vitreous humour of the eye before the subretinal injection,52 and the administration of Parkinson disease therapy is intracerebral.34 Administration of cellular therapies involving HSCT and CAR-Ts require pre-treatment conditioning, such as myeloablation to diminish immune reaction; specialized procedures such as leukapheresis to harvest and isolate cells; and shipment of cells to and from the primary care centre and the manufacturing facility. In addition, gene therapy recipients often require supportive care in case of adverse events.

Ultimately, given the technical and skill requirements, it may prove more feasible to offer gene therapy at a limited number of centres, as is currently done for transplants. In this case, however, travel and prolonged stays for patients and their caregivers may be required. Experiences in developing the processes and infrastructure for HSC transplants should help to inform the development of those for gene therapies. With refinements, standardization, and technical innovation, eventually data or isolated cells might be transmitted to a manufacturing centre and virus or transfected cells returned, but there will still be a need for specialized care before, during, and after treatment.10,29

In addition, for many diseases, early diagnosis and treatment minimizes irreversible damage and disability. Once therapies become available, screening programs (e.g., neonatal screening for metabolic disorders) may have to be expanded to include treatable conditions. Such screening would ensure the best possible individual and societal benefit but would further impact on system capacity and costs.29

The cost of gene therapies may place them outside the reach of health care systems in developing nations, with implications for international aid. In developed nations, rare genetic diseases are unevenly distributed across subpopulations, some of whom may be socially or economically disadvantaged, e.g., sickle cell anemia appears predominantly in people of African descent, and ADA-SCID occurs more frequently in First Nations and Mennonite groups.29 It will be essential to consider the specific needs of various population groups when making overall decisions.

For cell therapy–based technologies, transparency on the downstream commercialization of the cells, subsequent control rights, data protection, and privacy are needed. Risks and benefits associated with each technology should be considered from different stakeholders’ perspectives, and this information should be communicated appropriately to the intended patients.144

Another important ethical issue concerns the potential misuse of gene-modifying technologies for genetic enhancements. National laws vary considerably in what they prohibit, and many jurisdictions have not yet addressed this concern.149 On the other hand, the communal nature of DNA, the availability of gene-modifying technology (albeit not at the stage of established drugs or medical devices), and continuing scientific advances offer an argument in favour of gene therapy.150

Canadian Gene Therapy Initiatives

Canadian researchers are or have been involved in numerous gene therapy trials, including two of the three trials for alipogene tiparvovec for monogenic lipoprotein lipase deficiency,151-153 which has a high prevalence in Quebec due to a founder effect. Current gene therapy trials are listed in Health Canada’s Clinical Trials Database.2 A few of the initiatives supporting translational research and implementation of gene therapy or active production of gene therapy products are the following:

The Conconi Family Immunotherapy Lab, in BC Cancer’s Deeley Research Centre in Victoria, British Columbia, which has been established to provide custom immunotherapy production for cancer patients in British Columbia, in the form of CAR T-cells and oncogene-targeted T cells154

BioCanRx,155 a network of stakeholders formed to develop cancer immunotherapies through their support of educational initiatives, early clinical trials, and initiatives to address socioeconomic considerations for their adoption, including the Getting better Outcomes with Chimeric Antigen Receptor T cell therapy (GO–CART) program156

Centre de commercialisation en immunotherapie du cancer, at the Hôpital Maisonneuve-Rosemont, which is part of the Centres intégrés universitaires de santé et de services sociaux (CIUSS) de l’Est-de-l’Ile-de-Montréal.157

In Canada, gene therapy is expected to develop within a strong existing environment supporting stem cell therapeutics and regenerative medicine, transfusion and blood donation, and the treatment of cancer and rare diseases. Groups with a possible supportive role include the Stem Cell Network (national), Centre for Commercialization of Regenerative Medicine (national), Regenerative Medicine and Cell Therapy Network (CellCAN, national), Cell and Tissue Therapy Network (ThéCell, Quebec), Ontario Institute for Regenerative Medicine, the Canadian National Transplant Program and Transplant Registry, and the Canadian Association of Provincial Cancer Agencies.158

Final Remarks

  • Gene therapy technologies offer an alternative, and often the only alternative treatment option for patients with advanced ailments or rare genetic conditions.
  • Recently approved products and fast-track regulatory review for many technologies are offering hope of benefit for those affected by these conditions. Continued product development and refinement, monitoring of long-term clinical efficacy and safety, and development of frameworks for the assessment of these technologies are important for continued momentum.
  • The unique characteristics of gene therapy offer new treatment opportunities but will also pose new challenges to the health care system. An open dialogue among all relevant stakeholders is crucial to overcoming these hurdles.
  • The unique characteristics of gene therapy offer new treatment opportunities but will also pose new challenges to the health care system. An open dialogue among all relevant stakeholders is crucial to overcoming these hurdles.

References

  1. ClinicalTrials.gov by U.S National Library of Medicine [Database on the Internet]. 2018; https://clinicaltrials.gov/ct2/home.
  2. Health Canada's Clinical Trials Database. [Database on the Internet]. 2018; https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/health-canada-clinical-trials-database.html. Accessed March 2018.
  3. US Food and Drug Administration. What is gene therapy. https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ucm573960.htm. Accessed January 21, 2018, 2018.
  4. Ridgway A. Regulation of gene therapy: the Canadian approach. Biologicals : journal of the International Association of Biological Standardization. 1995;23(1):31-36.
  5. Ridgway A, Agbanyo F, Wang J, Rosu-Myles M. Regulatory Oversight of Cell and Gene Therapy Products in Canada. Advances in experimental medicine and biology. 2015;871:49-71.
  6. Health Canada. Guidance document: Preparation of clinical trial applications for use of cell therapy products in humans. In: Ottawa (ON): Government of Canada; 2015: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/clinical-trials/guidance-document-preparation-clinical-trial-applications-use-cell-therapy-products-humans.html. Accessed March 2018.
  7. Halioua-Haubold CL, Peyer JG, Smith JA, et al. Regulatory Considerations for Gene Therapy Products in the US, EU, and Japan. The Yale journal of biology and medicine. 2017;90(4):683-693.
  8. Carvalho M, Sepodes B, Martins AP. Regulatory and Scientific Advancements in Gene Therapy: State-of-the-Art of Clinical Applications and of the Supporting European Regulatory Framework. Frontiers in medicine. 2017;4:182.
  9. Dunbar CE, High KA, Joung JK, Kohn DB, Ozawa K, Sadelain M. Gene therapy comes of age. Science (New York, NY). 2018;359(6372).
  10. Shim G, Kim D, Park GT, Jin H, Suh SK, Oh YK. Therapeutic gene editing: delivery and regulatory perspectives. Acta pharmacologica Sinica. 2017;38(6):738-753.
  11. Amer MH. Gene therapy for cancer: present status and future perspective. Molecular and cellular therapies. 2014;2:27.
  12. Duffy MR, Fisher KD, Seymour LW. Making Oncolytic Virotherapy a Clinical Reality: The European Contribution. Human gene therapy. 2017;28(11):1033-1046.
  13. Wirth T, Parker N, Yla-Herttuala S. History of gene therapy. Gene. 2013;525(2):162-169.
  14. Marsden GT, A; Pearson, SD; Dreitlein, B; Henshall, C. . Gene Therapy: Understanding the science, assessing the evidence, and paying for value. 2017; https://icer-review.org/wp-content/uploads/2017/03/ICER-Gene-Therapy-White-Paper-030317.pdf, 2018.
  15. MIT NEWDIGS Initiative. Existing gene therapy pipeline likely to yield dozens of approved products within five years 2017F211.v011. MIT NEWDIGS Research Brief 2017F211.v011 2017; https://newdigs.mit.edu/sites/default/files/FoCUS_Research_Brief_2017F211v011.pdf, 2018.
  16. FDA. Designating an Orphan Product: Drugs and biological products. 2017; https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/default.htm. Accessed January 26, 2018, 2018.
  17. FDA. Fast Track. 2018; https://www.fda.gov/ForPatients/Approvals/Fast/ucm405399.htm. Accessed January 26, 2018, 2018.
  18. FDA. Breakthrough Therapy. 2018; https://www.fda.gov/ForPatients/Approvals/Fast/ucm405397.htm. Accessed January 26, 2018, 2018.
  19. FDA. Priority Review. 2018; https://www.fda.gov/ForPatients/Approvals/Fast/ucm405405.htm. Accessed January 26, 2018, 2018.
  20. FDA. Rare Pediatric Disease Priority Review Voucher Program. 2017; https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/RarePediatricDiseasePriorityVoucherProgram/default.htm. Accessed January 26, 2018, 2018.
  21. European Medicines Agency. Orphan designation. 2018; http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000029.jsp. Accessed January 26, 2018, 2018.
  22. European Medicines Agency. PRIME: Priority medicines. 2018; http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000029.jsp. Accessed January 26, 2018, 2018.
  23. Health Canada. Guidance for Industry - Priority Review of Drug Submissions. In: Ottawa, ON, Canada: Government of Canada; 2009: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/priority-review/drug-submissions.html.
  24. Health Canada. Guidance Document: Notice of Compliance with Conditions (NOC/c). In: Ottawa, ON, Canada: Government of Canada; 2015: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/notice-compliance-conditions.html.
  25. Gene Therapy: International Regulatory and Health Technology Assessment Activities and Reimbursement Status.
  26. Voretigene Neparvovec: An Emerging Gene Therapy for the Treatment of Inherited Blindness. Ottawa: CADTH; 2018 Feb. (CADTH issues in emerging health technologies; issue 169.
  27. Boye SE, Boye SL, Lewin AS, Hauswirth WW. A comprehensive review of retinal gene therapy. Molecular therapy : the journal of the American Society of Gene Therapy. 2013;21(3):509-519.
  28. Motta I, Scaramellini N, Cappellini MD. Investigational drugs in phase I and phase II clinical trials for thalassemia. Expert Opinion on Investigational Drugs. 2017;26(7):793-802.
  29. Xu X, Tailor CS, Grunebaum E. Gene therapy for primary immune deficiencies: a Canadian perspective. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology. 2017;13:14.
  30. Guggino WB, Cebotaru L. Adeno-Associated Virus (AAV) gene therapy for cystic fibrosis: current barriers and recent developments. Expert Opinion on Biological Therapy. 2017;17(10):1265-1273.
  31. Quon BS, Rowe SM. New and emerging targeted therapies for cystic fibrosis. BMJ (Clinical research ed). 2016;352:i859.
  32. Greenberg B. Novel Therapies for Heart Failure- Where Do They Stand? Circulation journal : official journal of the Japanese Circulation Society. 2016;80(9):1882-1891.
  33. Lahteenvuo J, Yla-Herttuala S. Advances and Challenges in Cardiovascular Gene Therapy. Human gene therapy. 2017;28(11):1024-1032.
  34. Piguet F, Alves S, Cartier N. Clinical Gene Therapy for Neurodegenerative Diseases: Past, Present, and Future. Human gene therapy. 2017;28(11):988-1003.
  35. Deng HX, Wang Y, Ding QR, Li DL, Wei YQ. Gene therapy research in Asia. Gene therapy. 2017;24(9):572-577.
  36. Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390(10097):849-860.
  37. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-Cell lymphoma. New England Journal of Medicine. 2017;377(26):2531-2544.
  38. Maude S, Teachey D, Rheingold S, et al. Durable remissions after monotherapy with CD19-specific chimeric antigen receptor (CAR)-modified T cells in children and young adults with relapsed/refractory all. Haematologica. 2016;101:183-184.
  39. Kumar SR, Markusic DM, Biswas M, High KA, Herzog RW. Clinical development of gene therapy: results and lessons from recent successes. Molecular therapy Methods & clinical development. 2016;3:16034.
  40. Howe SJ, Mansour MR, Schwarzwaelder K, et al. Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. The Journal of clinical investigation. 2008;118(9):3143-3150.
  41. Grimm D, Buning H. Small But Increasingly Mighty: Latest Advances in AAV Vector Research, Design, and Evolution. Human gene therapy. 2017;28(11):1075-1086.
  42. FDA. FDA approves first-of-its-kind product for the treatment of melanoma. December 19 2017; https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm589467.htm, 2018.
  43. Amgen Inc. European Commission Approves Amgen's IMLYGIC™ (talimogene laherparepvec) As First Oncolytic Immunotherapy In Europe 2015; http://www.amgen.com/media/news-releases/2015/12/european-commission-approves-amgens-imlygic-talimogene-laherparepvec-as-first-oncolytic-immunotherapy-in-europe/. Accessed January 26, 2018, 2018.
  44. FDA. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. 2017; https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm589467.htm.
  45. Novartis Media Relations. Novartis reaches another regulatory milestone for CTL019 (tisagenlecleucel) with submission of its MAA* to EMA for children, young adults with r/r B-cell ALL and adult patients with r/r DLBCL. 2017; https://www.novartis.com/news/media-releases/novartis-reaches-another-regulatory-milestone-ctl019-tisagenlecleucel-submission. Accessed January 26, 2018, 2018.
  46. Novartis Media Relations. Novartis submits application to FDA for KymriahTM (tisagenlecleucel) in adult patients with r/r DLBCL, seeking second indication for first-ever FDA approved CAR-T therapy. 2017; https://www.novartis.com/news/media-releases/novartis-reaches-another-regulatory-milestone-ctl019-tisagenlecleucel-submission. Accessed January 26, 2018, 2018.
  47. Gilead Sciences Inc. Gilead Sciences Inc. 2018; http://www.gilead.com/. Accessed January 26, 2018, 2018.
  48. Kite Pharma. YESCARTA(TM) (axicabtagene ciloleucel) Prescribing information. In. Santa Monica, CA, US: Kite Pharma; 2017.
  49. Kite Pharma. Kite Files the Industry's First CAR-T Marketing Authorization Application in Europe for Axicabtagene Ciloleucel. 2017; http://ir.kitepharma.com/releasedetail.cfm?releaseid=1035076. Accessed 2018.
  50. FDA. FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss. 2017; https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm589467.htm, 2018.
  51. National Library of Medicine (US). Leber congenital amaurosis Genetics Home Reference 2013; https://ghr.nlm.nih.gov/condition/leber-congenital-amaurosis. Accessed January 16, 2018.
  52. Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017(pagination).
  53. Spark Therapeutics. Spark Therapeutics Submits Marketing Authorization Application to European Medicines Agency for Investigational LUXTURNA™ (voretigene neparvovec). 2017; http://ir.sparktx.com/news-releases/news-release-details/spark-therapeutics-submits-marketing-authorization-application. Accessed January 26, 2018, 2018.
  54. MIT Technology Review. A Year After Approval, Gene-Therapy Cure Gets Its First Customer. May 3, 2017; https://www.technologyreview.com/s/604295/a-year-after-approval-gene-therapy-cure-gets-its-first-customer/. Accessed 2018.
  55. AAVRh.10 Administered to Children With Late Infantile Neuronal Ceroid Lipofuscinosis. In: ClinicalTrials.gov; 2018: https://ClinicalTrials.gov/show/NCT01414985. Accessed 2018.
  56. AveXis Inc. Gene Replacement Therapy Clinical Trial for Patients With Spinal Muscular Atrophy Type 1. In: ClinicalTrials.gov; 2018: https://ClinicalTrials.gov/show/NCT03306277. Accessed 2018.
  57. Open-Label Single Ascending Dose of Adeno-associated Virus Serotype 8 Factor IX Gene Therapy in Adults With Hemophilia B. In: Clinicaltrials.gov; 2018: https://ClinicalTrials.gov/show/NCT01687608. Accessed 2018.
  58. MolMed S.p.a. TK008: Efficacy Study on the Strategy of HSV-Tk Engineering Donor Lymphocytes to Treat Patients With High Risk Acute Leukemia. In: ClinicalTrials.gov; 2016: https://clinicaltrials.gov/ct2/show/NCT00914628. Accessed 2018.
  59. Safety Study of Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase to Treat Pompe Disease. In.
  60. TissueGene Inc. A Study to Determine the Safety and Efficacy of TG-C in Subjects With Kellgren and Lawrence Grade 2 or 3 OA of the Knee. In: ClinicalTrials.gov; 2017: https://clinicaltrials.gov/ct2/show/NCT03203330. Accessed January 31, 2018.
  61. Nationwide Children's Hospital. Systemic Gene Delivery Clinical Trial for Duchenne Muscular Dystrophy. In: ClinicalTrials.gov; 2018: https://ClinicalTrials.gov/show/NCT03375164. Accessed 2018.
  62. Farkas AM, Mariz S, Stoyanova-Beninska V, et al. Advanced Therapy Medicinal Products for Rare Diseases: State of Play of Incentives Supporting Development in Europe. Frontiers in medicine. 2017;4:53.
  63. uniQure announces it will not seek marketing authorization renewal for Glybera in Europe [press release]. April 20, 2017 2017.
  64. National Library of Medicine (US). Leber hereditary optic neuropathy. Genetics Home Reference 2013; https://ghr.nlm.nih.gov/condition/leber-hereditary-optic-neuropathy. Accessed January 16, 2018.
  65. GenSight Biologics. Efficacy and Safety Study of Bilateral Intravitreal Injection of GS010 for the Treatment of Vision Loss up to 1 Year From Onset in LHON Due to the ND4 Mutation (REFLECT). In: ClinicalTrials.gov; 2018: https://ClinicalTrials.gov/show/NCT03293524. Accessed 2018.
  66. GenSight Biologics. Efficacy Study of GS010 for the Treatment of Vision Loss up to 6 Months From Onset in LHON Due to the ND4 Mutation (RESCUE). In: ClinicalTrials.gov; 2018: https://ClinicalTrials.gov/show/NCT02652767. Accessed 2018.
  67. National Library of Medicine (US). Choroideremia. Genetics Home Reference 2013; https://ghr.nlm.nih.gov/condition/choroideremia. Accessed January 16, 2018.
  68. National Library of Medicine (US). Hemophilia. Genetics Home Reference 2013; https://ghr.nlm.nih.gov/condition/hemophilia. Accessed January 16, 2018.
  69. Biomarin. Single-Arm Study To Evaluate The Efficacy and Safety of Valoctocogene Roxaparvovec in Hemophilia A Patients at a Dose of 4E13 vg/kg. In: ClinicalTrials.gov; 2018: https://ClinicalTrials.gov/show/NCT03392974. Accessed 2018.
  70. Biomarin. Single-Arm Study To Evaluate The Efficacy and Safety of Valoctocogene Roxaparvovec in Hemophilia A Patients. In: ClinicalTrials.gov; 2018: https://ClinicalTrials.gov/show/NCT03370913. Accessed 2018.
  71. uniQure. uniQure. http://www.uniqure.com/. Accessed January 20, 2018, 2018.
  72. National Library of Medicine (US). Spinal muscular atrophy. Genetics Home Reference 2013; https://ghr.nlm.nih.gov/condition/spinal-muscular-atrophy. Accessed January 16, 2018.
  73. Cardium T. Taxus Cardium Pharmaceuticals Group. 2018; http://www.cardiumthx.com/. Accessed January 21, 2018, 2018.
  74. Angionetics. Next Study Ad5FGF-4 In Patients With Refractory Angina Due to Myocardial Ischemia (AFFIRM). In: Vol 2018. ClinicalTrials.gov; 2018: https://www.clinicaltrials.gov/ct2/show/NCT02928094. Accessed January 21, 2018.
  75. Renova. Renova Therapeutics. 2018; https://renovatherapeutics.com/. Accessed January 21, 2018, 2018.
  76. Renova. AC6 Gene Transfer in Patients With Reduced Left Ventricular Ejection Fraction Heart Failure (FLOURISH). In: ClinicalTrials.gov; 2018: https://www.clinicaltrials.gov/ct2/show/NCT03360448. Accessed January 21, 2018.
  77. VBL. VBL Therapeutics. 2018; http://www.vblrx.com/.
  78. Vascular Biogenics Ltd. A phase 3, pivotal trial of VB-111 plus bevacizumab vs. bevacizumab in patients with recurrent glioblastoma (GLOBE). 2017; https://www.clinicaltrials.gov/ct2/show/NCT02511405.
  79. Vascular Biogenics Ltd. A study of VB-111 with paclitaxel versus paclitaxel for treatment of recurrent platinum-resistant ovarian cancer (OVAL). 2018; https://www.clinicaltrials.gov/ct2/show/NCT03398655.
  80. SillaJen. SillaJen Inc. 2018; http://www.sillajen.com/eng/main/main.aspx. Accessed January 21, 2018, 2018.
  81. SillaJen Inc. Hepatocellular Carcinoma Study Comparing Vaccinia Virus Based Immunotherapy Plus Sorafenib vs Sorafenib Alone (PHOCUS). In: Clinical Trials.gov; 2018: https://www.clinicaltrials.gov/ct2/show/NCT02562755?term=Pexa-Vec&phase=2&rank=1. Accessed January 21, 2018.
  82. AnGes USA Inc. Efficacy and Safety of AMG0001 in Subjects With Critical Limb Ischemia (AGILITY). In: ClinicalTrials.gov; 2018: https://www.clinicaltrials.gov/ct2/show/NCT02144610. Accessed January 23, 2018.
  83. ViroMed Co. Ltd. dba VM BioPharma. Safety and Efficacy Study of VM202 in the Treatment of Chronic Non-Healing Foot Ulcers. In: ClinicalTrials.gov; 2018: https://www.clinicaltrials.gov/ct2/show/NCT02563522. Accessed January 23, 2018.
  84. ViroMed Co. Ltd. dba VM BioPharma. Phase 3 Gene Therapy for Painful Diabetic Neuropathy. In: ClinicalTrials.gov; 2018: https://www.clinicaltrials.gov/ct2/show/NCT02427464. Accessed January 23, 2018.
  85. ViroMed Co. Ltd. dba VM BioPharma. Safety and Efficacy Study Using Gene Therapy for Critical Limb Ischemia. In: ClinicalTrials.gov; 2018: https://clinicaltrials.gov/ct2/show/NCT01064440. Accessed January 23, 2018.
  86. Safety Study of an Adeno-associated Virus Vector for Gene Therapy of Leber's Hereditary Optic Neuropathy. In: ClinicalTrials.gov; 2018: https://ClinicalTrials.gov/show/NCT02161380.
  87. bluebird bio. A Study Evaluating the Efficacy and Safety of the LentiGlobin® BB305 Drug Product in Subjects With Transfusion-Dependent β-Thalassemia, Who do Not Have a β0/β0 Genotype. In: ClinicalTrials.gov; 2017: https://clinicaltrials.gov/ct2/show/NCT02906202. Accessed January 31, 2018.
  88. bluebird bio. A Study Evaluating the Safety and Efficacy of the LentiGlobin BB305 Drug Product in Severe Sickle Cell Disease. 2017; https://clinicaltrials.gov/ct2/show/NCT02140554. Accessed January 31, 2018, 2018.
  89. bluebird bio. A Study Evaluating the Efficacy and Safety of LentiGlobin BB305 Drug Product in Beta-Thalassemia Major and Sickle Cell Disease. In: ClinicalTrials.gov; 2017: https://clinicaltrials.gov/ct2/show/NCT02151526. Accessed January 31, 2018.
  90. bluebird bio. A Phase 2/3 Study of the Efficacy and Safety of Hematopoietic Stem Cells Transduced With Lenti-D Lentiviral Vector for the Treatment of Cerebral Adrenoleukodystrophy (CALD). 2018; https://clinicaltrials.gov/ct2/show/NCT01896102. Accessed January 31, 2018, 2018.
  91. Eichler F, Duncan C, Musolino P, et al. Interim results from a phase 2/3 study of the safety and efficacy of hematopoietic stem cells transduced ex vivo with lentiviral vector (lenti-D) for cerebral adrenoleukodystrophy. Annals of Neurology. 2016;80:S414.
  92. GlaxoSmithKline. A Safety and Efficacy Study of Cryopreserved GSK2696274 for Treatment of Metachromatic Leukodystrophy (MLD). In: ClinicalTrials.gov; 2018: https://clinicaltrials.gov/ct2/show/NCT03392987. Accessed January 31, 2018.
  93. Spark Therapeutics. A Gene Therapy Study for Hemophilia B. In: ClinicalTrials.gov; 2018: https://ClinicalTrials.gov/show/NCT02484092. Accessed 2018.
  94. National Library of Medicine (US). Mucopolysaccharidosis type III. Genetics Home Reference 2013; https://ghr.nlm.nih.gov/condition/mucopolysaccharidosis-type-iii. Accessed January 16, 2018.
  95. Abeona Therapeutics Inc. Phase I/II Gene Transfer Clinical Trial of scAAV9.U1a.hSGSH. In: ClinicalTrials.gov: https://www.clinicaltrials.gov/ct2/show/NCT02716246. Accessed 30 January 2018.
  96. National Library of Medicine (US). Duchenne and Becker muscular dystrophy. Genetics Home Reference 2013; https://ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy. Accessed January 16, 2018.
  97. Nationwide Children's Hospital. Follistatin Gene Transfer to Patients With Becker Muscular Dystrophy and Sporadic Inclusion Body Myositis. In: CinicalTrials.gov; 2018: https://ClinicalTrials.gov/show/NCT01519349. Accessed 30 January 2018.
  98. Greenberg B, Butler J, Felker GM, et al. Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial. Lancet. 2016;387(10024):1178-1186.
  99. Juno Therapeutics Inc. Study Evaluating Safety and Efficacy of JCAR017 in Subjects With Relapsed or Refractory CLL or SLL (TRANSCEND-CLL-004). In: ClinicalTrials.gov; 2018: https://www.clinicaltrials.gov/ct2/show/NCT03331198. Accessed January 31, 2018.
  100. Juno Therapeutics Inc. Study Evaluating the Safety and Pharmacokinetics of JCAR017 in B-cell Non-Hodgkin Lymphoma (TRANSCEND-NHL-001). In: ClinicalTrials.gov; 2017: https://www.clinicaltrials.gov/ct2/show/NCT02631044. Accessed January 31, 2018.
  101. bluebird bio. Bluebird Bio. https://www.bluebirdbio.com/.
  102. bluebird bio. Efficacy and Safety Study of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma (KarMMa) (bb2121). In: ClinicalTrials.gov; 2018: https://www.clinicaltrials.gov/ct2/show/NCT03361748. Accessed January 31, 2018.
  103. bluebird bio. Study of bb2121 in multiple myeloma. In: ClinicalTrials.gov; 2018: https://www.clinicaltrials.gov/ct2/show/NCT02658929. Accessed January 31, 2018.
  104. DNAtrix Therapeutics. DNAtrix Therapeutics. 2018; http://www.dnatrix.com/. Accessed January 21, 2018, 2018.
  105. DNAtrix Inc. Combination Adenovirus + Pembrolizumab to Trigger Immune Virus Effects (CAPTIVE). In: ClinicalTrials.gov; 2018: https://www.clinicaltrials.gov/ct2/show/NCT02798406. Accessed January 21, 2018.
  106. Targovax. Targovax. 2018; http://www.targovax.com/Home/default.aspx. Accessed January 21, 2018, 2018.
  107. Targovax Oy. A Randomised Phase II Open-label Study With a Phase Ib Safety lead-in Cohort of ONCOS-102, an Immune-priming GM-CSF Coding Oncolytic Adenovirus, and Pemetrexed/Cisplatin in Patients With Unresectable Malignant Pleural Mesothelioma. In: ClinicalTrials.gov; 2018: https://www.clinicaltrials.gov/ct2/show/NCT02879669. Accessed January 21, 2018.
  108. Virtuu Biologics. Virtuu Biologics. 2018; http://www.virttu.com/. Accessed January 21, 2018, 2018.
  109. Virtuu Biologics. Intrapleural Administration of HSV1716 to Treat Patients With Malignant Pleural Mesothelioma. (1716-12). In: ClinicalTrials.gov; 2018: https://www.clinicaltrials.gov/ct2/show/NCT01721018. Accessed January 21, 2018.
  110. Inc T. No One Should Die of Cancer | Cancer-Selective Gene Therapy | Tocagen. 2018; https://tocagen.com/. Accessed March 8, 2018.
  111. University of Pennsylvania. Screening Protocol for a Gene Therapy Trial in Subjects With Homozygous Familial Hypercholesterolemia. In: ClinicalTrials.gov: https://ClinicalTrials.gov/show/NCT03018678. Accessed 30 January 2018.
  112. Weill Medical College of Cornell University. Safety Study of a Gene Transfer Vector (Rh.10) for Children With Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL). In: ClinicalTrials.gov; 2018: https://ClinicalTrials.gov/show/NCT01161576. Accessed 30 January 2018.
  113. Tocagen Inc. The Toca 5 Trial: Toca 511 & Toca FC Versus Standard of Care in Patients With Recurrent High Grade Glioma (Toca5). 2018; https://clinicaltrials.gov/ct2/show/NCT02414165. Accessed January 31, 2018, 2018.
  114. Adaptimmune. A Pilot Study of Genetically Engineered NY-ESO-1 Specific NY-ESO-1ᶜ²⁵⁹T in HLA-A2+ Patients With Synovial Sarcoma (NY-ESO-1). 2017; https://clinicaltrials.gov/ct2/show/NCT01343043. Accessed January 31, 2018, 2018.
  115. Adaptimmune. Redirected Auto T Cells for Advanced Myeloma. In: ClinicalTrials.gov; 2017: https://clinicaltrials.gov/ct2/show/NCT01352286. Accessed January 31, 2018.
  116. University of California Los Angeles. Autologous Cryopreserved CD34+ Hematopoietic Cells Transduced With EFS-ADA Lentivirus for ADA SCID. In: ClinicalTrials.gov; 2017: https://clinicaltrials.gov/ct2/show/NCT02999984. Accessed January 31, 2018.
  117. Adaptimmune. NY-ESO TCR: OVERVIEW. 2018; https://www.adaptimmune.com/pipeline/ny-eso-tcr. Accessed February 5 2018.
  118. Genethon. WAS > Genethon. 2018; http://www.genethon.fr/en/products/was/. Accessed January 31, 2018, 2018.
  119. Genethon. Gene Therapy for X-linked Chronic Granulomatous Disease (X-CGD) (CGD). In: ClinicalTrials.gov; 2017: https://clinicaltrials.gov/ct2/show/NCT01855685. Accessed January 31, 2018.
  120. Genethon. Gene Therapy for WAS Follow-up (WAS FUP). In: ClinicalTrials.gov; 2016: https://clinicaltrials.gov/ct2/show/NCT02333760. Accessed January 31, 2018.
  121. Sangamo Therapeutics. Product pipeline::Sangamo Therapeutics. 2018; https://www.sangamo.com/product-pipeline. Accessed January 31, 2018, 2018.
  122. PD-1 Knockout Engineered T Cells for Advanced Esophageal Cancer.
  123. PD-1 Knockout EBV-CTLs for Advanced Stage Epstein-Barr Virus (EBV) Associated Malignancies.
  124. A Study Evaluating UCART019 in Patients With Relapsed or Refractory CD19+ Leukemia and Lymphoma.
  125. Institute for Clinical and Economic Review. Chimeric Antigen Receptor T-Cell Therapy for BCell Cancers: Effectiveness and Value. December 21 2017; https://icer-review.org/wp-content/uploads/2017/07/ICER_CAR_T_Draft_Evidence_Report_121917.pdf. Accessed 2018.
  126. Scutti S. Gene therapy for rare retinal disorder to cost $425,000 per eye. 2018; https://www.cnn.com/2018/01/03/health/luxturna-price-blindness-drug-bn/index.html. Accessed January 31, 2018, 2018.
  127. FDA. Spark Therapeutics. Luxturna (voretigene neparvovec-rzyl) Full prescribing information. 2017; https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM589541.pd
  128. Amgen Inc. FDA Approves IMLYGIC™ (Talimogene Laherparepvec) As First Oncolytic Viral Therapy In The US. 2015; http://www.amgen.com/media/news-releases/2015/10/fda-approves-imlygic-talimogene-laherparepvec-as-first-oncolytic-viral-therapy-in-the-us/. Accessed January 31, 2018, 2018.
  129. Grady D. F.D.A. Approves First Gene-Altering Leukemia Treatment, Costing $475,000. The New York Times. August 30, 2017, 2017.
  130. Novartis receives first ever FDA approval for a CAR-T cell therapy, Kymriah(TM) (CTL019), for children and young adults with B-cell ALL that is refractory or has relapsed at least twice. August 30 2017; https://www.novartis.com/news/media-releases/novartis-receives-first-ever-fda-approval-car-t-cell-therapy-kymriahtm-ctl019, 2018.
  131. FDA. KYMRIAH™ (tisagenlecleucel) suspension for intravenous infusion [package insert]. 2017; https://www.fda.gov/downloads/UCM573941.pdf, 2018.
  132. FDA approval brings first gene therapy to the United States. August 30 2017; https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm, 2018.
  133. With FDA Approval for Advanced Lymphoma, Second CAR T-Cell Therapy Moves to the Clinic. October 25 2017; https://www.cancer.gov/news-events/cancer-currents-blog/2017/yescarta-fda-lymphoma, 2018.
  134. FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma. October 18 2017; https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm581216.htm, 2018.
  135. YESCARTA™ (axicabtagene ciloleucel) suspension for intravenous infusion [package insert].  https://www.fda.gov/downloads/UCM581226.pdf. Accessed 2018.
  136. Spark Therapeutics. Spark Therapeutics. 2018; www.sparktx.com. Accessed January 20, 2018, 2018.
  137. Human Stem Cells Instutute. Human Stem Cells Institute. 2018; https://eng.hsci.ru/home. Accessed January 23, 2018, 2018.
  138. AveXis Inc. Study of Intrathecal Administration of AVXS-101 for Spinal Muscular Atrophy. In: ClinicalTrials.gov; 2017: https://ClinicalTrials.gov/show/NCT03381729. Accessed 6 February 2018.
  139. Milo Biotechnology. Clinical Intramuscular Gene Transfer of rAAV1.CMV.huFollistatin344 Trial to Patients With Duchenne Muscular Dystrophy. In: ClinicalTrials.gov; 2017: https://ClinicalTrials.gov/show/NCT02354781. Accessed January 25, 2018.
  140. Shanghai Sunway Biotech Co Ltd. http://www.sunwaybio.com.cn/en/index.html. 2018; http://www.sunwaybio.com.cn/en/index.html. Accessed January 23, 2018, 2018.
  141. Clinica Universidad de Navarra--Universidad de Navarra. Oncolytic Adenovirus, DNX-2401, for Naive Diffuse Intrinsic Pontine Gliomas. In: ClinicalTrials.gov; 2017: https://clinicaltrials.gov/ct2/show/NCT03178032. Accessed January 29, 2018.
  142. AnGes MG. HOME - AnGes, Inc. 2018; https://www.anges.co.jp/en/.
  143. ViroMed Co. Ltd. Safety Study of VM202 to Treat Amyotrophic Lateral Sclerosis. In: ClinicalTrials.gov; 2018: https://clinicaltrials.gov/ct2/show/NCT02039401. Accessed January 29, 2018.
  144. Hanna E, Remuzat C, Auquier P, Toumi M. Gene therapies development: slow progress and promising prospect. Journal of market access & health policy. 2017;5(1):1265293.
  145. Auricchio A, Smith AJ, Ali RR. The Future Looks Brighter After 25 Years of Retinal Gene Therapy. Human gene therapy. 2017;28(11):982-987.
  146. Mullin E. Tracking the cost of gene therapy. In. MIT Technology Review2017.
  147. Hanna E, Dorey J, Aballéa S, Auquier P, Toumi M. Will Stem Cells For Heart Failure Be The Next Sofosbuvir Issue? Value in Health.19(7):A656.
  148. Hanna E, Zhou J, Cheng X, et al. Advanced Therapy Medicinal Products for Alzheimer's Disease Will Shrink the National Health Service Budget. Value in Health.19(7):A523.
  149. Ledford H. Where in the world could the first CRISPR baby be born? Nature. 2015;526(7573):310-311.
  150. Harrison PT, Hoppe N, Martin U. Gene editing & stem cells. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2018;17(1):10-16.
  151. Bryant LM, Christopher DM, Giles AR, et al. Lessons learned from the clinical development and market authorization of Glybera. Human gene therapy Clinical development. 2013;24(2):55-64.
  152. Gaudet D, Methot J, Dery S, et al. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial. Gene therapy. 2013;20(4):361-369.
  153. Stroes ES, Nierman MC, Meulenberg JJ, et al. Intramuscular administration of AAV1-lipoprotein lipase S447X lowers triglycerides in lipoprotein lipase-deficient patients. Arteriosclerosis, thrombosis, and vascular biology. 2008;28(12):2303-2304.
  154. BC Cancer Foundation. Immunotherapy | Current Cancer Research | BC Cancer Foundation.  https://bccancerfoundation.com/your-donations-work/current-cancer-research/immunotherapy. Accessed March 2, 2018.
  155. BioCanRx. Home page - BioCanRx.  https://biocanrx.com/. Accessed March 2, 2018.
  156. BioCanRx. CSEI Lalu - BioCanRx.  https://biocanrx.com/csei-lalu.
  157. Centre for commercialization of cancer immunotherapy. Centre C3i - Centre C3i.  https://centrec3i.com/en/home/. Accessed March 2, 2018.
  158. Council of Canadian Academics. Building on Canada’s Strengths in Regenerative Medicine. Ottawa, ON, Canada: Council of Canadian Academics.

About This Document

Authors: Alison Sinclair, Saadul Islam, Sarah Jones

Cite as: Gene therapy: an overview of approved and pipeline technologies. Ottawa: CADTH; 2018 Mar. (CADTH issues in emerging health technologies; issue 171).

Acknowledgments: Louis de Léséleuc, Jeff Mason, Teo Quay, Joanne Kim, Lesley Dunfield, Eftyhia Helis, Iryna Magega, Jane Hurge

ISSN: 1488-6324 (online)

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