Gene Therapy Platform for Rare Diseases

National Center For Advancing Translational Sciences

Investigators

Linked publications, trials & patents

Abstract

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. Bioanalytical 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 and an engineering lot. 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. In the past year, the first batch of current Good Manufacturing Process (cGMP)-compliant material has been manufactured. An efficacy and safety study in PA mouse model has been completed. Additionally, a GLP toxicology study to demonstrate safety has been completed. A Type C meeting with the FDA was held in Dec 2024 to discuss surrogate biomarkers and gain feedback related to CMC strategy for the clinical lots. Preparation of IND documentation is underway for submission to the FDA. Lead candidate finalization, proof-of-concept studies, small-scale process development, ODD and RPDD applications for MMAB were previously completed. Scale-up manufacturing with production of feasibility and engineering batches was conducted in the past year. To further advance this program, preparation for a pre-IND meeting with the FDA is ongoing; cGMP manufacturing and GLP toxicology studies are in the planning stage. COLQ and DOK7 are in early stages of development. In the past year, the lead candidate for both COLQ and DOK7 was finalized. Animal natural history studies were completed for COLQ and efficacy testing in animal models and manufacturing process development are ongoing. For DOK7, the proof-of-concept studies were initiated, and manufacturing plans are underway. Finally, clinical trial activities have commenced this year, including the development of clinical protocols and the initiation of operations for study implementation at the NIH Clinical Center. Bioanalytical assay development was completed and qualification of the methods for immunogenicity testing is in progress. The first dissemination milestone for PaVe-GT was achieved in 2023 with release of the ODD and RPDD regulatory packages, templates and a white paper outlining how to successfully navigate this process. Release of the INTERACT meeting experience and regulatory documentation is currently underway. The white paper has been published, and website updates are in progress. Additional dissemination activities are in progress, including white papers sharing experience, release of templates and learnings from efficacy studies, manufacturing activities and pre-IND/ Type C meeting. Platform activities are underway, including development of an open-access platform for AAV manufacturing, immunogenicity methods, and others.