ALPHA-GLUCOSIDASE ENHANCEMENT IN POMPE DISEASE

Pompe disease (Glycogenosis type II) is an inherited metabolic disorder due to the deficiency of the enzyme alpha-glucosidase. The enzyme deficiency results in tissue accumulation of glycogen. The clinical picture of the disease shares similarities with neuromuscular disorders, with a severe hypertrophic cardiomyopathy and muscle hypotonia eventually leading to respiratory failure. The aim of this study is to evaluate the effects of specific small molecules on alpha-glucosidase activity in cells from patients with Pompe disease, and to provide the rationale for a possible alternative therapeutic approach to this inherited metabolic disorder, such as enzyme enhancement (EE). The effects on skeletal muscle of enzyme replacement therapy (ERT), currently employed in clinical trials as a therapy for Pompe disease, appear variable. There is experimental evidence suggesting that skeletal muscle involvement may not be completely reverted by ERT. Alternative therapeutic approaches, such as EE, may be of help particularly in the treatment of patients with the non-classic infantile and late onset forms of Pompe disease, characterized by a major involvement of skeletal muscle without significant cardiomyopathy. In the proposed study the enhancement effect on alpha-glucosidase activity of specific small molecules, such as iminosugars, will be investigated, as well as the mechanism implicated in the enhancing effect. It is possible that this research may indicate the feasibility of EE in infantile non-classic and late-onset Pompe disease, as a therapeutic option alternative to ERT.