693P Proposed NIH core for advanced genetic therapies: spotlight on clinical development of AAV products for neuromuscular disorders

• Published in: Neuromuscular disorders : NMD Vol. 43; p. 104441
• Main Authors: Todd, J., Reoma, L., Nath, A., Martin, S., Brooks, K., Ano, S., Dukhanina, O., Lawal, T., Brooks, P., Ottinger, E., Lomash, R., Stan, R., Goldfeder, L., Venditti, C., Bönnemann, C.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.10.2024
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2024.07.196

The genetic (gene and transcript-directed) therapies field is burgeoning, with >700 gene therapies in development. Approximately a quarter use AAV for transgene delivery and U.S. FDA anticipate 10-20 approvals annually by 2025. Since 2012, intramural NINDS has actively engaged in clinical development of genetic therapies at the NIH Clinical Center through investigator-initiated studies and collaboration with industry and nonprofits. AAV programs at NINDS have included first-in-human intrathecal gene transfer for Giant Axonal Neuropathy, a phase 2/3 systemic gene transfer trial for X-linked myotubular myopathy, and a first-in-human MRI-guided putaminal gene therapy trial delivering GDNF for Parkinson's disease. Numerous AAV gene therapy trials for neuromuscular disorders are expected to launch in the near term at the NIH Clinical Center including through collaborative efforts such as the Platform Vector Gene Therapy Program (PaVe-GT: DOK7 and COLQ congenital myasthenic syndromes) and Bespoke Gene Therapy Consortium (BGTC: SPG50 and CMT4J). There is also broad demand for a centralized clinical research support infrastructure to achieve programmatic efficiency across the 27 NIH Institutes/Centers, ensure timely patient access to investigational genetic therapies, harmonize long-term follow-up processes, and de-risk early phase clinical development to maximize (a) the prospect of future commercialization through public-private partnerships or (b) provide a sustainable model for NIH-sponsored open INDs. Initially, the proposed Core for Advanced Genetic Therapies (CAGT) anticipates providing direct support of 6 clinical protocols poised to begin enrolling patients in 2024-25, including a multi-institute master protocol for long-term follow-up of AAV gene transfer products, and clinical trials for 2 inborn errors of metabolism and 3 neuromuscular disorders. We present a framework for implementation of rare disease genetic therapy trials at a dedicated center.