Pompe disease is a potentially fatal metabolic myopathy caused by the deficiency of lysosomal acid ?- glucosidase (GAA; EC 3.2.1.20) that leads to accumulation of lysosomal glycogen and muscle damage. The only currently available treatment consists of enzyme replacement therapy (ERT) with recombinant human GAA, which requires frequent treatments with high lifetime costs. Genome editing in Pompe disease, conversely, could permanently correct mutations in the GAA gene and ameliorate patient symptoms. The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 system has emerged as a promising tool to edit genomes with high precision. However, previous studies that used this system for mutation correction through homologous recombination required the transduction of each cell with two adeno- associated virus (AAV) vectors with relatively low efficiency, in comparison with using a single AAV vector as proposed here. Given that AAV vectors do not uniformly transduce muscle, the efficiency with which two vectors transduce individual muscle cells is low; therefore, the application of this technology to correct mutations in Pompe disease has not been possible. We propose to develop a genome editing system using a single AAV vector to correct the biochemical abnormalities and muscle weakness in Pompe disease. We will correct two of the most common GAA gene variants. Genome editing in Pompe disease will permanently correct GAA and continuously express GAA ameliorating patient symptoms and represents a major advancement for the treatment of Pompe patients.
Improved therapy for Pompe disease will advance the treatment of a rare, orphan disease, representing an unmet medical need. Furthermore, genome editing for Pompe disease could potentially provide adjunctive therapy for other lysosomal storage disorders.
