Gene Therapy Platform for Rare Diseases

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The learnings from the initial projects provided TRND with a robust foundation to contribute to a new NCATS-led initiative, the Platform Vector Gene Therapy (PaVe-GT) pilot project. PaVe-GT seeks to increase the efficiency of clinical trial startup by using the same gene delivery system and manufacturing methods for multiple rare disease gene therapies. This collaborative, trans-NIH initiative includes partners from NCATS, the National Human Genome Research Institute (NHGRI), the National Institute of Neurological Disorders and Stroke (NINDS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). PaVe-GT will develop gene therapies for four diseases: two congenital myasthenic syndromes (Dok7 deficiency; ColQ deficiency) and two organic acidemias (propionic acidemia (PA); cobalamin type B methylmalonic acidemia (MMAB)). All will be based on the adeno-associated virus (AAV)-9 capsid. TRND scientists are conducting the preclinical development necessary to advance all four therapies to clinical testing in patients. To date, a lead AAV-9 gene therapy candidate has been identified for treating PCCA-related PA. Proof of concept studies have demonstrated efficacy of the lead candidate in PA animal models. Bioanalytic assay development is ongoing, and pilot batches of the lead candidate have been manufactured. Scale-up of the product manufacturing process has been completed with production of a feasibility lot. Engineering lot manufacturing is ongoing; efficacy, and toxicology studies to demonstrate safety are in the planning phase. Early regulatory feedback on the development plan for the first AAV9-hPPCA gene product was obtained through an INTERACT meeting with the FDA followed by a pre-IND meeting to gain feedback on the manufacturing process, planned IND-enabling studies, and clinical study design. In addition, Orphan Drug Designation (ODD) and Rare Pediatric Drug Designations (RPDD) have been received for the AAV9-hPCCA gene therapy product. Identification of the lead candidates, animal model natural history studies, proof of concept studies, and manufacturing of pilot batches are in progress for the other three disease indications under the PaVe-GT umbrella. Efforts for development of an open access platform for AAV production are in progress. The first dissemination milestone for PaVe-GT was achieved this year with release of the ODD and RPDD regulatory packages, templates and a white paper outlining how to successfully navigate this process. Finally, clinical trial activities, including clinical protocol preparations and operations for study implementation at the NIH Clinical Center have been initiated.