COMBINED ENZYME ENHANCEMENT THERAPY (EET) AND ENZYME REPLACEMENT THERAPY (ERT) IN PATIENTS WITH POMPE DISEASE

PD is a metabolic myopathy, caused by the deficiency of a lysosomal enzyme acid-alpha-glucosidase (GAA). The clinical manifestation of the disease are a severe cardiomypathy and progressive muscle weakness. At present a treatment is available for PD, enzyme replacement therapy (ERT), based on the periodic intravenous infusion of recombinant human GAA (rhGAA). However, ERT, although successful in reverting cardiac involvement and improving muscle function in some patients, has limitations. Specifically, correction of the enzyme defect and of function in skeletal muscle is insufficient in several patients. We propose the combined use of a novel therapeutic approach, enzyme enhancement therapy (EET) with pharmacological chaperones, and ERT. We recently provided the rationale for this approach in collaboration with TIGEM. In this study we propose to treat PD patients followed at four Italian centers involved in the care of metabolic disease with ERT and the pharmacological chaperone NB-DNJ (Miglustat, Zavesca), already approved for clinical use for a different indication. As short-term endpoints we plan to see whether the combination of these approaches can increase the efficacy of ERT. This study may provide the proof that combination therapies are more effective in correcting the enzymatic deficiency of a debilitating genetic disorder, such as PD. This model may be extended to other lysosomal diseases in which ERT is available, but has limited efficacy.