Joining forces to increase effective gene therapies for rare diseases

Approximately 7,000 rare diseases have been identified, affecting as many as 30 million Americans, according to the National Institutes of Health (NIH) in the United States, but gene therapies have received US Food and Drug Administration (FDA) approval for only two inherited diseases. However, in unity there is strength: the FDA and NIH are partnering with 15 private organisations to increase the numbers of effective gene therapies for rare diseases.

The Bespoke Gene Therapy Consortium (BGTC), which is part of the NIH Accelerating Medicines Partnership (AMP) programme and project managed by the Foundation for the National Institutes of Health (FNIH), has also been formed. The goals of BGTC are “to optimise and streamline the gene therapy development process to help fill the unmet medical needs of people with rare diseases.”

The 10 private partners in this endeavour are Biogen; Janssen Research & Development; Novartis Institutes for BioMedical Research; Pfizer; Regenxbio; Spark Therapeutics; Takeda Pharmaceutical Company; Taysha Gene Therapies; Thermo Fisher Scientific; and Ultragenyx Pharmaceutical. They are joined by five non-profit partners: Alliance for Regenerative Medicine; American Society of Gene & Cell Therapy; CureDuchenne; National Organization for Rare Disorders; and National Institute for Innovation in Manufacturing Biopharmaceuticals.

“Most rare diseases are caused by a defect in a single gene that could potentially be targeted with a customised or ‘bespoke’ therapy that corrects or replaces the defective gene,” said former NIH Director Dr Francis S. Collins. “There are now significant opportunities to improve the complex development process for gene therapies that would accelerate scientific progress and, most importantly, provide benefit to patients by increasing the number of effective gene therapies.”

Standardisation: key to efficiency

Developing gene therapies is a highly complex process that is time-consuming and expensive. In addition, the development process has limited access to tools and technologies and no standards across the field, and only one disease is addressed at a time. A standardised therapeutic development model with a common gene delivery technology (i.e., a vector) would facilitate a more efficient approach to developing gene therapies.

“By leveraging on experience with a platform technology and by standardising processes, gene therapy product development can be accelerated to allow more timely access to promising new therapies for patients who need them most,” said Dr Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research.

A primary aim of BGTC is to improve the understanding of the basic biology of a common gene delivery vector, the adeno-associated viral (AAV) vector. The investigators plan to examine the biological and mechanistic steps involved in AAV vector production, delivery of genes via vectors into human cells, and how therapeutic genes are activated in target cells. The results of this will provide important information to improve the efficiency of vector manufacturing and enhance the overall therapeutic benefit of AAV gene therapy.

BGTC will also develop a standard set of analytic tests to apply to the manufacture of AAV vectors created by the investigators, with the goals of improving and accelerating the processes of vector manufacturing and production processes. Such tests could be broadly applicable to different manufacturing methods and make the process of developing gene therapies for very rare conditions much more efficient.

BGTC will then fund four to six clinical trials focused on different rare diseases that result from single-gene mutations and currently have no gene therapies or commercial programmes under development. Different types of AAV vector that have been employed in previous clinical trials will be used in these trials.

BGTC will also aim to shorten the path from studies in animal models of disease to human clinical trials, whilst another of its aims is finding ways to streamline regulatory requirements and processes for the FDA approval of safe and effective gene therapies, including developing standardised approaches to pre-clinical testing (e.g., toxicology studies).

Further AMP projects

BGTC is the first AMP initiative to focus on rare diseases. Other AMP projects bring together scientific talent and financial resources from academia, industry, philanthropy and government, and focus on improving the productivity of therapeutic development for common metabolic diseases, schizophrenia, Parkinson’s disease, Alzheimer’s disease, type 2 diabetes and autoimmune rheumatoid arthritis.

Dr Luk Vandenberghe, director of the Grousbeck Gene Therapy Center and the Grousbeck Family Chair in Gene Therapy at Massachusetts Eye and Ear and associate professor of ophthalmology at Harvard Medical School in Boston, said that the consortium effort around bespoke gene therapies led by the FDA and FNIH and supported by several leading industry group is timely and needed.

“Gene therapy has shown to be particularly powerful for many inherited disorders that by nature are rare,” he said. “Over the past years, through academia and industry efforts, the technology has shown its remarkable potential; however, the development of gene therapies for many diseases stalls due to the limited number of patients.”

According to Dr Vandenberghe, the small number of patients brings practical challenges in conducting trials, and also a limited commercial appeal – which, together, limit investments in gene therapies for these very rare indications.

“This sad irony is particularly true for inherited retinal degenerations (IRDs), caused by over 200 genetic aetiologies of disease and thus arguably in need of distinct solutions for each of them,” he concluded. “On the one side, Luxturna [voretigene neparvovec-rzyl, Spark Therapeutics], an IRD gene therapy, was the first FDA-approved AAV gene therapy, but on the other side, similar programmes for other retinal disorders with equally compelling biology struggle to move forward in development due to their low prevalence.”

Luk H. Vandenberghe, PhD

E: luk_vandenberghe@meei.harvard.edu

Dr Vandenberghe is a consultant to Novartis Gene Therapies and Albamunity, Inc. He holds patents for AAVCOVID and various AAV and adeno gene therapy and vaccine technologies, for which he receives royalties from University of Pennsylvania and Mass General Brigham, US.