New therapeutic approaches for Pompe disease: enzyme replacement therapy and beyond.

Pompe disease is an autosomal recessive disorder of glycogen metabolism caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). Prior to 2006, therapy was palliative. Severely affected infants with Pompe succumbed to cardiomyopathy or respiratory failure by one year of age. Enzyme replacement therapy (ERT) with alglucosidase alfa (Genzyme, Cambridge, MA, USA) is currently the only approved treatment for Pompe disease which has improved overall survival, ventilator-free survival, cardiomyopathy, and motor development in infants. In patients with late onset Pompe disease, ERT has resulted in disease course stabilization with motor and pulmonary improvements. Factors impacting outcome include age at start of ERT, muscle fiber type, underlying genotype and a multidisciplinary approach to care. This article highlights the lessons learned from infants and adults treated with ERT, limitations of ERT, and the development of adjunctive and alternative therapies, including immune modulation, upregulation of receptor expression, diet and exercise, second-generation recombinant ERT, chaperone therapy, substrate reduction therapy and gene therapy.