Stable therapy in Pompe disease through genome editing

The need for treatment early in life has emerged as an unmet need in Pompe disease (acid maltase deficiency; glycogen storage disease type II), a lysosomal storage disorder caused by acid -glucosidase (GAA) deficiency that leads to the accumulation of lysosomal glycogen and debilitating weakness. Patients with Pompe disease receive life-prolonging therapy with enzyme replacement therapy (ERT) consisting of recombinant human GAA; however, ERT fails to completely reverse symptoms including glycogen storage and functional deficits. The lack of a complete response to ERT has stimulated the development of new therapies, including gene therapy. Gene therapy development has largely overlooked the need for early treatment during preclinical research. We propose to address the question of how gene therapy for Pompe disease can reverse nervous system involvement through the following Specific Aims: 1) Translate genome editing that establishes a stable depot for GAA to the liver early in life; 2) Evaluate personalized genome editing for the treatment of Pompe disease early in life. Developing gene therapy in Pompe disease may provide benefits in comparison with ERT, including the correction of skeletal muscle and enhanced quality of life. These Specific Aims will address the need for treatment early in life in Pompe disease by developing genome editing, which will guide the design of future clinical trials to develop highly effective genetic therapy.