Phase 1/2 Study of Clenbuterol for the Treatment of Pompe Disease

描述（由申请人提供）：

DESCRIPTION (provided by applicant): Pompe disease is a myopathy, similar to limb-girdle muscular dystrophy in its late-onset form. It results from acid alpha-glucosidase (GAA) deficiency in striated and smooth muscle, which leads to the accumulation of lysosomal glycogen and destruction of skeletal, smooth and cardiac muscle. Enzyme replacement therapy (ERT) with recombinant human GAA has shown stabilization of the disease process from a pulmonary and motor perspective in late onset Pompe disease. However, the limitations of ERT have become apparent, including high dosage requirements and the lack of complete reversal of muscle weakness and pulmonary involvement in adult patients. A gradual clinical decline and increased mortality has emphasized the need for new therapy to improve the outcome of these patients. Lysosomal storage disorders such as Pompe disease may be more effectively treated, if the hurdle of cation-independent mannose-6-phosphate receptor (CI-MPR) uptake can be cleared. The paucity of CI-MPR in adult mammals' muscle has underscored the concept that CI-MPR is limiting for ERT in Pompe disease. Low levels of CI-MPR have been demonstrated in skeletal muscle of GAA knockout mice, specifically in muscles comprised primarily of type II myofibers. Preliminary results in a mouse model revealed that beta-2 agonist therapy enhanced CI-MPR expression and increased efficacy from GAA replacement therapy, thereby confirming the key role of CI-MPR with regard to replacement therapy in Pompe disease. This application proposes a 52 week placebo-controlled, double-blind study of the beta-2 agonist clenbuterol as an adjunctive therapy to ERT in 20 adult patients with late onset Pompe disease. Specific Aim 1 of the study is to determine the safety and efficacy of clenbuterol as adjunctive therapy. This initial evaluation will include muscle strength testing, the 6 minute walk test, and pulmonary function testing. Evaluation of safety will include standard blood testing and electrocardiograms, while on study drug. Specific Aim 2 of the study is to determine the effect of clenbuterol therapy upon receptor-mediated uptake of recombinant GAA in patients. The effects of clenbuterol upon CI-MPR expression will be evaluated. The impact of enhanced CI-MPR mediated uptake of GAA will be analyzed by comparing muscle function and biochemical correction of glycogen accumulation in muscle at baseline and during clenbuterol administration. The urinary biomarker glucose tetrasaccharidde (Glc4), will be monitored. These studies are being done to determine if there are any correlations between biochemical correction and clinical endpoints.