Targeting the root cause of mucopolysaccharidosis IIIA with a new scAAV9 gene replacement vector

Abstract No treatment is available to address the unmet needs of MPS IIIA patients. Targeting the root cause, we developed a new scAAV9 vector to deliver the human N-sulfoglucosamine sulfohydrolase (hSGSH) gene driven by a mini CMV (mCMV) promoter. In pre-clinical studies, the vector was tested at varying doses by a single IV infusion into MPS IIIA mice at different ages. The vector treatments resulted in rapid and long-term expression of functional rSGSH enzyme and elimination of lysosomal storage pathology throughout the CNS and periphery in all tested animals. Importantly, MPS IIIA mice treated with the vector at up to 6m of age showed significantly improved behavior performance in a hidden task in the Morris water maze, and extended lifespan with the majority of the animals surviving within the normal range, indicating that the vector treatment can prevent and reverse MPS IIIA disease progression. Notably, 2.5x1012vg/kg was functionally effective. Further, the vector treatment did not lead to detectable systemic toxicity or adverse events in MPS IIIA mice. These data demonstrate the development of a safe and effective new gene therapy product for treating MPS IIIA, which further support the extended clinical relevance of platform rAAV9 gene delivery for treating broad neurogenetic diseases.