A novel AAV capsid with improved CNS tropism for treating Pompe disease by intravenous administration

Pompe disease is a lysosomal storage disorder caused by a deficiency in acid alpha-glucosidase (GAA) activity that results in the accumulation of glycogen in the lysosome. The disease presents as a form of muscular dystrophy which primarily affects both smooth and striated musculature as well as the central nervous system (CNS), with early mortality. Enzyme replacement therapy (ERT) is currently the only FDA-approved therapy to treat Pompe and requires bi-weekly injections of relatively large quantities of recombinant protein. While ERT significantly reduces the mortality rate of infantile Pompe patients, who typically die by the age of two without therapy, it fails to completely ameliorate all symptoms of Pompe, primarily due to its inability to efficiently enter the CNS and resulting immune responses to the GAA protein. Gene therapy strategies have been investigated and while many show great promise in correcting the glycogen accumulation and other symptoms of Pompe, most have suffered from the severe immune response seen during GAA replacement. Previous work has demonstrated that hepatic-specific expression can tolerize animals to the GAA protein and significantly reduce the humoral response. We have identified a novel adeno-associated virus (AAV) capsid with improved tissue specificity and expression in the target tissues, namely heart, muscle and CNS after intravenous administration. We have developed a novel codon-optimized transgene and improved promoter for supraphysiological expression levels in target tissues as well as increased secretion for cross-correction to non-transduced cells. Proof of concept studies demonstrate significant protein expression and enzymatic activity en route to IND-enabling studies.