Development of gene therapy product for treating MPS IIIB

Project Summary The goal of this fast-track SBIR project is to further develop AAV gene therapy product for treating Mucopolysaccharidosis (MPS) IIIB towards clinical application and commercialization. MPS IIIB, is a rare autosomal recessive lysosomal storage disease (LSD) caused by defects in α-N- acetylglucosaminidase (NAGLU), a lysosomal enzyme essential for the degradation of heparan sulfates, a class of biologically important glycosaminoglycans (GAGs). The lack of NAGLU activity results in lysosomal GAG storage in cells in virtually all organs, leading to severe neurological manifestations, broad somatic disorders and premature death. No treatment is available for MPS IIIB. Gene therapy (GT) targeting the root cause has been considered to be an ideal strategy for treating monogenic diseases including LSDs. Numerous studies have demonstrated the success of systemic trans-BBB-neurotropic AAV9 gene delivery for treating neurogenetic diseases. Importantly, the efficacy and safety profiles of systemic rAAV9 gene delivery have been demonstrated to be highly reproducible across different LSDs. To address the unmet need, we developed new GT products for MPS IIIB, using the AAV9 vector platform to deliver a codon-optimized human NAGLU cDNA (hNAGLUop). The codon-optimization resulted in enhanced expression and rNAGLU secretion, indicating the potential for added by-stander effects. In preliminary studies, we tested these in MPS IIIB mice and were able to identify the optimal vector product for further development. With an IV injection of the designated optimal rAAV9-hNAGLUop vector in MPS IIIB mice, we achieved functional correction and reversal of neurological and somatic disorders of MPS IIIB, strongly support the therapeutic potential of the proposed rAAV9-hNAGLUop vector product for treating MPS IIIB in humans. We believe that we are well-positioned to move forward towards a Phase I/II IND. In order to efficiently develop the rAAV9-hNAGLUop GT product, this Fast-Track SBIR proposal will address the critical challenge in developing AAV GT, the scale-up vector manufacturing. In Phase I studies, we will perform the engineering trials of the scale-up rAAV9-hNAGLUop vector manufacturing (Aim #1) to develop and optimize the procedures, based on the protocols and procedures currently used by Dr. Fu’s team. The vector products will be tested in vitro and in vivo for qualification and SOPs will be developed. Once validated, in Phase II, we will build a facility with two GMP manufacture suites using certified modular cleanrooms (Aim #2), in order to produce rAAV9-hNAGLUop vector for our planned IND and eventual clinical application and commercialization. In Phase II stage of this SBIR, we will also hold the Pre-IND meeting with the FDA for advice on our planned Phase I/II GT clinical trial and then submit the IND package to the FDA for approval (Aim #3). The success of this Fast-track SBIR project will enable the efficient development of the MPS IIIB GT product towards clinical application and commercialization.