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 gene vector design and manufacturing. These technologies, along with best practices to achieve regulatory approval of gene therapy, will help improve the speed of development and reduce costs for gene therapy in general. The pilot projects include preclinical development of therapies for Duchenne muscular dystrophy, Pompe disease, and aromatic L-amino acid decarboxylase (AADC) deficiency. Pompe disease: During the collaboration with TRND, the adeno-associated virus (AAV) gene therapy technology was licensed by Asklepios BioPharmaceutical, Inc. AskBio formed a spin-out company, Actus Therapeutics, to continue clinical development and commercialization. The key preclinical support provided by TRND enabled the lead collaborator (Dr. Dwight Koeberl) to initiate a phase I trial in Pompe disease patients (NCT03533673). TRND is co-funding the clinical trial through a cooperative agreement with the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). AADC deficiency: The team completed an end-of-phase 2 meeting with the U.S. Food and Drug Administration (FDA), to discuss the clinical data obtained from trials of AGIL-AADC conducted in Taiwan, and whether PTC Therapeutics could proceed to seeking U.S. market approval without requiring additional bridging trials in the U.S. The clinical package, plus key preclinical safety, biodistribution, and chemistry, manufacturing and controls data developed by TRND, led FDA to agree that PTC Therapeutics could proceed to file a Biologics Licensing Application (BLA) for marketing approval in the U.S. AGIL-AADC has received Orphan Drug and Rare Pediatric Disease designations in the U.S., as well as Orphan Medicinal Product status in Europe. The Orphan Drug designation provides access to the expedited Priority Review pathway at FDA. Ongoing research at TRND includes an effort to obtain DDC gene sequences from 3,000 randomly selected and deidentified newborn blood samples, with the potential to support an application to include the DDC gene in the recommended uniform screening panel. Duchenne muscular dystrophy: This collaboration involves developing novel manufacturing methods to scale up AAV production to treat a musculoskeletal condition. Transducing a sufficient number of skeletal muscle cells requires a very high number of vector genomes per patient. Current production methods cannot physically meet the needs for all DMD patients. We are experimenting with small molecule potentiators, suspension cells, insect cells, and producer cell lines to address this system-wide 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.