Liver targeted AAV8 gene therapy ameliorates skeletal and cardiovascular pathology in mucopolysaccharidosis IVA murine model

Abstract Mucopolysaccharidosis type IVA (MPS IVA) is due to the deficiency of GALNS and characterized by systemic skeletal dysplasia. We have evaluated AAV8 vectors expressing different forms of human GALNS under a liver-specific promoter. The vectors were delivered intravenously into 4-week-old MPS IVA knockout (KO) and immune tolerant (MTOL) mice at a dose of 5x1013 GC/kg. These mice were monitored for 12 weeks post-injection. GALNS enzyme activity was elevated significantly in plasma of all treated mice two weeks post-injection. The activity observed was 4-19-fold higher than that in wild-type mice and was maintained throughout the monitoring period. Treatment with AAV vectors resulted in a reduction of KS levels in plasma to normal levels two weeks post-injection, which were maintained until necropsy. Both vectors reduced the storage in articular cartilage, ligaments, and meniscus surrounding articular cartilage and growth plate region as well as heart muscle and valves. Our results suggest that the continuous presence of high levels of circulating enzyme increases the penetration into bone and heart and reduces KS level, thereby improving storage in these regions. The current data support a strategy for developing a novel treatment to address the bone and heart disease in MPS IVA using AAV gene therapy.