Challenges in treating Pompe disease: an industry perspective.

Pompe disease is a rare inherited metabolic disorder of defective lysosomal glycogen catabolism due to a deficiency in acid alpha-glucosidase (GAA). Alglucosidase alfa enzyme replacement therapy (ERT) using recombinant human GAA (rhGAA ERT) is the only approved treatment for Pompe disease. Alglucosidase alfa has provided irrefutable clinical benefits, but has not been an optimal treatment primarily due to poor drug targeting of ERT to skeletal muscles. Several critical factors contribute to this inefficiency. Some are inherent to the anatomy of the body that cannot be altered, while others may be addressed with better drug design and engineering. The knowledge gained from alglucosidase alfa ERT over the past 2 decades has allowed us to better understand the challenges that hinder its effectiveness. In this review, we detail the problems which must be overcome for improving drug targeting and clinical efficacy. These same issues may also impact therapeutic enzymes derived from gene therapies, and thus, have important implications for the development of next generation therapies for Pompe.