TH.O.17 - Whole-body rescue of Pompe disease with AAV liver delivery of engineered secretable GAA transgenes

Abstract

Pompe disease is a severe neuromuscular disorder caused by mutations in the lysosomal enzyme acid a-glucosidase (GAA), which result in the pathological accumulation of glycogen in all tissues. Enzyme replacement therapy (ERT) is available for Pompe disease, however it has limited efficacy, high immunogenicity, and fails to correct nervous tissue and muscle groups refractory to cross-correction. Using bioinformatics analysis and protein engineering, we developed secretable GAA transgenes for enhanced cross-correction of Pompe disease via adeno-associated virus (AAV) vector liver gene transfer. Pompe mice were treated with AAV vectors optimized for hepatic expression of secretable GAA transgenes and followed for up to 10 months. Gene transfer resulted in dose- and time- dependent whole-body correction of biochemical and functional defects in muscle, central nervous system and spinal cord, with normalization of cardiac hypertrophy, muscle and respiratory function, and survival undistinguishable from wild-type littermates. In these experiments, secretable GAA transgenes showed superior therapeutic efficacy and markedly low immunogenicity compared with their native GAA counterpart. Scale-up to non-human primates, and modeling of GAA expression in primary hepatocytes using hepatotropic AAV vector serotypes, demonstrate the therapeutic potential of AAV vector-mediated liver expression of secretable GAA transgenes, supporting the feasibility of the approach in Pompe patients.