Joining forces to increase the effectiveness of gene therapies against rare diseases

Reviewed by Luk H. Vandenberghe, PhD

There is strength in unity, and this philosophy should further stimulate the development of gene therapy for the millions of American patients with a rare disease.

The FDA and the National Institutes of Health (NIH) are partnering with 15 private organizations to increase the number of effective gene therapies for rare diseases that affect up to 30 million Americans.

About 7,000 rare diseases have been identified, but to date gene therapies have only received FDA approval for 2 inherited diseases.

This recognition led to the formation of the Bespoke Gene Therapy Consortium (BGTC), which is part of the NIH Accelerating Medicines Partnership (AMP) program and project managed by the Foundation for the National Institutes of Health (FNIH).

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The goals of the BGTC are “to optimize and streamline the process of developing gene therapy to help meet the unmet medical needs of people with rare diseases”.

The 10 private partners in this venture are Biogen Inc, Cambridge, Massachusetts; Janssen Research & Development, LLC, Raritan, New Jersey; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts; Pfizer Inc, New York, New York; Regenxbio Inc, Rockville, Maryland; Spark Therapeutics, Philadelphia, Pennsylvania; Takeda Pharmaceutical Company Limited, Deerfield, Illinois; Taysha Gene Therapies, Dallas, Texas; Thermo Fisher Scientific Inc, Waltham, Massachusetts; and Ultragenyx Pharmaceutical, Novato, California.

They are joined by 5 nonprofit partners: Alliance for Regenerative Medicine, Washington, DC; American Society for Gene and Cell Therapy, Milwaukee, Wisconsin; CureDuchenne, Newport Beach, California; National Organization for Rare Diseases, Quincy, Massachusetts; and National Institute for Innovation in Manufacturing Biopharmaceuticals, Newark, Delaware.

“Most rare diseases are caused by a defect in a single gene that could potentially be targeted by personalized or ‘tailor-made’ therapy that corrects or replaces the defective gene,” said NIH Director Francis S. Collins, MD, PhD. “There are now significant opportunities to improve the complex development process of gene therapies that would accelerate scientific progress and, above all, bring benefits to patients by increasing the number of effective gene therapies. “

Standardization: the key to technology

The development of gene therapies is a very complex, long and expensive process. In addition, the development process has limited access to tools and technologies and no standards in the field, and 1 disease is treated at a time. A standardized 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 the experience of a platform technology and standardizing processes, gene therapy product development can be accelerated to enable faster access to promising new therapies for patients who have the need more, ”said Peter Marks, MD, PhD, director of the FDA Center for Biologics Assessment and Research.

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

Related: POAAGG Study Targets Gene Therapy Options For Glaucoma

The BGTC will also develop a standard set of analytical tests to be applied to the manufacture of AAV vectors created by researchers with the aim of improving and accelerating the manufacturing and production processes of vectors. Such tests could be widely applicable to different manufacturing methods and make the process of developing gene therapies for very rare conditions much more efficient.

The BCTC will then fund 4-6 clinical trials focusing on different rare diseases resulting from mutations of a single gene and currently having no gene therapy of commercial programs under development. Different types of AAV vectors will be used in assays that were used in previous clinical trials. For these trials, the BGTC will aim to shorten the path between studies in animal models of disease and clinical trials in humans.

Another function of the BGTC is to find ways to streamline regulatory requirements and FDA approval processes for safe and effective gene therapies, including developing standardized approaches for preclinical testing (eg, toxicology studies).

BGTC is AMP’s first 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 for common metabolic diseases and systemic lupus erythematosus.

Luk H. Vandenberghe, PhD, 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 the consortium’s effort around Customized gene therapies led by the FDA and FNIH and supported by several leading industry groups are timely and necessary.

“Gene therapy has been shown to be particularly powerful for many inherited diseases which are inherently rare,” he said. “In recent years, thanks to the efforts of academia and industry, technology has shown its remarkable potential; However, the development of gene therapies for many diseases has stalled due to the limited number of patients.

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

“This sad irony is especially true for hereditary retinal degeneration. [IRDs], caused by more than 200 genetic etiologies of diseases and therefore undoubtedly need separate solutions for each of them, ”he concluded. “On the one hand, Luxturna [voretigene neparvovec-rzyl, Spark Therapeutics, Inc], an IRD gene therapy, was the first AAV gene therapy approved by the FDA, but on the other hand, similar programs for other retinal disorders with equally convincing biology are struggling to move forward in the development due to their low prevalence.

Luk H. Vandenberghe, PhD

E: luk_vandenberghe@meei.harvard.edu

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