Gene Therapy R&D Accelerates

Gene Therapy R&D Accelerates

December 06, 2019PAP-Q4-19-NI-002
The Promise and Challenges of Gene and Gene-Modified Cell Therapies

The Breakthrough Issue Feature: Part 1 

Since the first discoveries suggesting that gene therapy might be possible, the field has experienced significant advances and setbacks. Research efforts have expanded greatly in recent years following the development of safer viral vectors and the advent of gene-editing technologies. The possibilities seem endless, and many companies are exploring them.

Several Approved Products

Successful gene therapies address significant unmet medical needs, have clear mechanisms of action and can readily reach the target organ.1 Several gene therapies, including cell therapies that have been genetically modified, have met these criteria and reached the market.

As of October 2018, Pharma Intelligence had identified 11 gene therapies that had been approved in China, South Korea, Russia, Europe and the United States.2 However, not all are currently on the market. The first was approved in 2015 in China, but most have been approved in the EU and United States within the last three years. Some have been withdrawn due to limited sales. Since then, Novartis’ Zolgensma (onasemnogene abeparvovec-xioi) for spinal muscular atrophy was approved in the United States, and bluebird bio’s Zynteglo (autologous CS34+ cells encoding the ßA-T87Q- globin gene) for transfusion-dependent ß-thalassemia received conditional marketing authorization in Europe.

Numerous Growth Drivers

The successes achieved with these approved gene and gene-modified cell therapies and the potential for these products to cure — rather than just treat — serious conditions has driven significant investment in the sector. Venture capital and large and mid-sized pharma companies are actively funding startups and more established firms focused on developing novel gene therapies, as well as investing in their own programs.2 During just the first half of 2019, gene and gene-modified cell therapy companies raised $4.3 billion.3

Regulatory agencies have also established approval pathways and provided guidance on regenerative medicines, including gene and gene-modified cell therapies.2 The European Medicines Agency created a regulatory framework for advanced therapy medicinal products (ATMPs) in 2007, while the U.S. Food and Drug Administration implemented the accelerated regenerative medicine advanced therapy (RMAT) designation in 2016.

As a result, the value of the global market for genetic modification therapies is growing at a record pace. Various market research firms estimate a CAGR for the sector of 20–50%, with most estimates in the 30–40% range,1,4-9 with the global value projected to surpass $5 billion by 2026.6,9

Strong Clinical Pipeline

The rich clinical pipeline of gene-modified therapies is also driving rapid growth in the sector.1 According to the Alliance for Regenerative Medicine, 366 gene therapy and 410 gene-modified cell therapy clinical trials were underway at the end of the first half of 2019, accounting for nearly 75% of all regenerative medicine trials.3 The bulk (55%) of the studies were phase II trials, followed by phase I (39%) and phase III (6%). Many of the therapies in phase III development could be commercialized by the end of 2020,5 and as many as three quarters of products in early clinical development could reach the market by the late 2020s.6

Along with the rapid rise in numbers of clinical trials has been an increase in the number of gene and cell therapy–related journal articles, patents and substances registered by the Chemical Abstracts Service (CAS). CAS reports that, of the 6500 substances registered in the last 30 years, most were added in the last 10 years, with 600 added in the first six months of 2018.10

The FDA, meanwhile, currently is processing 800 cell-based or directly administered gene therapy INDs and expects to receive more than 200 gene and gene-modified cell therapy INDs per year beginning in 2020.11 Furthermore, the agency predicts that it will approve 10–20 cell and gene therapy products per year based on an assessment of the current pipeline and the clinical success rates of these products.

In Vivo and Ex Vivo

Gene and gene-modified cell therapies differ in the method used to modify the target cells. Gene therapies are in vivo treatments in which the targeted genes or genetic modifications are administered directly into cells that are inside the body. Gene-modified cell therapies are ex vivo treatments in which cells, either from the patient (autologous or patient-specific) or a healthy donor (allogeneic or off-the-shelf) are genetically modified outside of the body, expanded and then administered to the patient.

According to Pharma Intelligence, approximately 55% of pipeline candidates are in vivo or gene therapies, and most of the ex vivo investigative therapies are autologous.2 Chimeric antigen receptor (CAR)-T cell therapy is the most widely investigated ex vivo approach, with leading biomarkers including CD19, CD20, HER2 and CD30, among others.10 Other cell types of interest for ex vivo therapies include natural killer (NK) cells, human stem cells (HSCs) and Listeria-based, tumor-infiltrating lymphocytes (TILs).1

Some gene therapies regulate the expression of genes through the delivery of RNA. The predominant technologies include RNA interference (RNAi), which halts production of disease-causing proteins; antisense interference, which inhibits or enhances translation of mRNA into target proteins; microRNA modulation (miRNA), which also inhibits or enhances translation of mRNA into proteins; and messenger RNA (mRNA), which generates therapeutic proteins.1 RNA therapies can also be in vivo or ex vivo.

Viral Vector Delivery Dominates

Regardless of the type of therapy, the genetic material must be delivered into cells using some type of delivery system. The choices fall into one of two categories: viral or nonviral.

The first gene therapies were developed using viral vectors, and this method dominates today (nearly 70% of candidates).2 Among viral vectors, adeno-associated viruses (AAVs) and lentiviruses (LVs) are most widely used owing to their reduced immunogenicity and long-term transgene expression.2 Other viruses investigated as potential vector technologies for gene delivery include retroviruses and gamma retroviruses, modified herpes simplex virus, adenoviruses, vaccinia virus and baculovirus.

Significant attention is being paid to the development of nonviral delivery technologies that eliminate the safety concerns associated with viral vectors. Examples include injection of naked DNA, electroporation, sonoporation, magnetofection and the use of oligonucleotides, lipoplexes, dendrimers or inorganic nanoparticles, which may also be more amenable to large-scale production.12 Most of these approaches exhibit lower transfection efficiencies, but progress is being achieved.

Gene Editing Advances

Gene editing, which relies on the use of engineered nucleases to modify genetic sequences, provides yet another approach to gene therapy development. In this case, the dysfunctional gene is manipulated or removed, rather than adding a functional gene and leaving the impaired genetic material in the cell. Advances in gene editing technologies have made it possible to more precisely repair errors in the genetic code and have led to acceptance of this technology for the development of new medicines.

The CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9) system has received the most attention, because it enables the efficient and precise insertion, deletion, modification or replacement of specific genes.10 Other technologies in use include transcription activator–like effector nucleases (TALENs), zinc finger nucleases (ZFNs) and meganuleases.1

There are significant concerns regarding the use of genetic editing in the development of new drugs, particularly with respect to off-targeting. Only in the last couple of years have candidates entered into clinical trials, and most target severe genetic diseases that are typically fatal, for which the benefits would dramatically outweigh the risks. Some of these gene therapies are designed to stop production of a protein (gene knockout), replace or repair a dysfunctional protein (gene correction) or start production of a new protein (gene insertion).1

Continued development of gene-editing technologies that have improved tissue targeting and greater specificity is ongoing, as is work to develop tools that are capable of editing multiple genes simultaneously, which would open the door for gene therapies that treat polygenic disorders, such as Alzheimer’s disease and diabetes.1

Focus on Oncology and Rare Diseases

Of the 1069 clinical trials underway for regenerative medicines, 60% address oncology indications, while 6% and 5%, respectively, target cardiovascular diseases and diseases of the central nervous
system.3 In addition, 266 companies are developing 563 gene and gene-modified cell therapies focused on rare diseases, 79% of which are for oncology indications, 6% for blood disorders and 5% for endocrine, metabolic and genetic disorders.

Plethora of Gene Therapy Developers

The companies developing gene therapies include both small biotechs and larger biopharmaceutical firms, with nearly 400 unique companies investigating development-stage candidates, according to Pharma Intelligence.2 Some have multiple candidates, such as REGENXBIO, Juno Therapeutics (acquired by Celgene) and Genethon. Others have just one or two. Sangamo Therapeutics, CRISPR Therapeutics, and Editas lead the list of companies focused on the development of gene-edited therapies.

Novartis (acquired AveXis), UniQure, Spark Therapeutics, bluebird bio and Kite Pharmaceuticals (acquired by Gilead) are some of the firms with approved gene therapies on the market.

Read Part 2: Overcoming the Manufacturing Roadblock
Read Part 3: Promise Amid Challenges:
Logistics of the Cell and Gene Therapy Supply Chain


  1. Sullivan, L.S. and J. Bergin. “Genetic Modification Therapies – Clinical Applications & Technology Platforms.” Drug Development & Delivery. Nov./Dec. 2018. Web.

  2. “Gene Therapy: A Paradigm Shift in Medicine.” Pharma Intelligence: Informa White Paper. Nov. 2018. Web.

  3. “Q2 2019 Quarterly Regenerative Medicine Global Data Report.” Rep. Alliance for Regenerative Medicine. 2019. Web.

  4. Global Cell and Gene Therapy Market to Surpass US$ 35.4 Billion by 2026. Coherent Market Insights. 5 Feb. 2019. Web.

  5. Gene Therapy Market Size, Share & Trends Analysis Report By Vector (Lentivirus, RetroVirus & Gamma RetroVirus), By Indication (Beta-Thalassemia Major/SCD, ALL, Large B-cell Lymphoma), And Segment Forecasts, 2019 – 2026. Rep. Grand View Research. Apr. 2019. Web.

  6. Gene Therapy Market Size Worth $5.55 Billion By 2026 | CAGR: 33.9%. Grand View Research. Apr. 2019. Web.

  7. Global $1.01 Billion Cell and Gene Therapy Market 2019-2025: Steady Investment and Consolidation in the Market. Research and Markets. 7 Aug. 2019. Web.

  8. Gene Therapy Market by Vector Type (Viral Vector and Non-viral Vector), Gene Type (Antigen, Cytokine, Tumor Suppressor, Suicide, Deficiency, Growth Factors, Receptors, and Others), and Applications (Oncological Disorders, Rare Diseases, Cardiovascular Diseases, Neurological Disorders, Infectious Disease, and Other Diseases) - Global Opportunity Analysis and Industry Forecast, 2017-2023. Rep. Allied Market Research. Feb. 2018. Web.

  9. Gene Therapy Market (Product - Yescarta, Kymriah, Luxturna, Strimvelis, Gendicine; Application - Ophthalmology, Oncology, Adenosine Deaminase Deficient Severe Combined Immunodeficiency (ADA-SCID)) - Global Industry Analysis, Size, Share, Growth, Trends, and Forecast 2018 – 2026. Rep. Transparency Market Research. Oct. 2018. Web.

  10. Liu, Cynthia. “Gene and cell therapy: The R&D and market insights you need to get a competitive edge,” Chemical Abstract Service Blog. 12 Apr. 2019. Web.

  11. “Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies.” U.S. Food and Drug Administration. 25 Jan. 2019. Web.

  12. Keeler, A.M., M.K. ElMallah and T.R. Flotte. “Gene Therapy 2017: Progress and Future Directions.” Clinical Translational Science. 6 Apr. 2017. Web.

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