Development of gene therapy product for treating MPS IIIB

Project Summary NeuroGT, Inc is a new start-up company founded by Dr. Haiyan Fu, Associate professor in the Gene Therapy Center at University of North Carolina at Chapel Hill, with the mission of develop and commercialize effective gene therapy products to treat rare neurogenetic diseases in humans. The goal of this project is to develop an effective gene therapy product targeting the root cause for treating Mucopolysaccharidosis (MPS) IIIB in humans. MPS IIIB is a fatal lysosomal storage disease (LSD) caused by autosomal recessive defects in α-N-acetylglucosaminidase (NAGLU), leading to severe neurological manifestations, broad somatic disorders and premature death. No effective treatment is available for MPS IIIB. Gene therapy targeting the root cause has been demonstrated to be an ideal strategy for treating monogenic diseases including LSDs. Our previous studies have led to IND approvals for Phase 1/2 GT clinical trials in patients with MPS IIIA (NCT02716246), MPS IIIB (NCT03315182), and MPS II (IND# 17838), using the trans- BBB-neurotropic AAV9 vector via a systemic delivery. For improved therapeutic potential, we have developed three new 2nd-generation (2nd-gen) gene therapy products for MPS IIIB, using the AAV9 platform to deliver a codon-optimized human NAGLU gene (hNAGLUop) driven by different promoters. The codon-optimization resulted in enhanced rNAGLU secretion, indicating the potential of added by-stander effects. We have tested one of the 2nd-gen rAAV9-hNAGLUop vector in mice via an IV injection, and shown that the vector treatment was safe and effective for treating MPS IIIB, supporting the potential of further development towards clinical application in humans. In this proposed project, with human translation and commercialization in mind, we will expand our efforts to test the efficacy and safety of these rAAV9-hNAGLUop products in mice via systemic delivery to generate rigorous preclinical data to support the IND submission and clinical development.Project Summary Gene therapy products using adeno-associated-virus (AAV) vector have shown promise for treating monogenetic diseases in humans. This project targets the unmet need for mucopolysaccharidosis (MPS) IIIB, a devastating fatal disease in children. The goal is to develop an effective gene therapy product targeting the root cause of the disease for the treatment of MPS IIIB in patients.