Gene Therapy Platform for Rare Diseases

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The TRND Program initiated a number of collaborations with biotech and academic groups that were selected to serve as pilot projects. The overall goal is to enable TRND to help address challenges in preclinical development, including gene vector design and manufacturing. Advancing these technologies, along with best practices to achieve regulatory approval of gene therapies, will help harmonize preclinical studies and approaches, aiming to improve the speed of development and reduce costs for gene therapy in general. The pilot projects included preclinical development of therapies for Duchenne muscular dystrophy, aromatic L-amino acid decarboxylase (AADC) deficiency and Pompe disease. TRND support enabled the initiation of a phase I trial in Pompe disease patients (NCT03533673) and positioned our collaborators to proceed to filing a Biologics Licensing Application (BLA) for AADC deficiency. Our continuing collaboration on Duchenne muscular dystrophy (DMD) involves developing novel manufacturing methods to scale up AAV production to treat a musculoskeletal condition. Transducing enough skeletal muscle cells requires a very high number of vector genomes per patient. Current production methods cannot produce the amount of product needed for all DMD patients. We are experimenting with small molecule potentiators, suspension cells, insect cells, and producer cell lines to address this systemwide production problem. The collaboration also explores large animal models of DMD, which are generally accepted as more translatable to the human disease condition. We are experimenting with CRISPR technology as a potential curative approach to DMD, as well as ways to predict safety parameters, particularly related to AAV- and Cas9-induced innate and adaptive immune responses in patients. The learnings from the individual gene therapy 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; cobalamin type B methylmalonic acidemia). 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.