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

描述（由申请人提供）： 庞贝氏症是一种肌病，类似于肢带型肌营养不良症的晚发形式。 它由横纹肌和平滑肌中的酸性α-葡糖苷酶（GAA）缺乏引起，这导致溶酶体糖原的积累和骨骼肌、平滑肌和心肌的破坏。 重组人GAA的酶替代疗法（ERT）从肺和运动的角度在晚发性庞贝氏症中显示出疾病过程的稳定。然而，ERT的局限性已经变得明显，包括高剂量要求和缺乏完全逆转成人患者的肌无力和肺部受累。 逐渐的临床下降和死亡率增加强调了需要新的治疗方法来改善这些患者的结局。如果能够清除阳离子非依赖性甘露糖-6-磷酸受体（CI-MPR）摄取的障碍，则可以更有效地治疗溶酶体贮积症（如庞贝氏症）。CI-MPR在成年哺乳动物肌肉中的缺乏强调了CI-MPR在庞贝氏症中限制ERT的概念。 在GAA敲除小鼠的骨骼肌中，特别是在主要由II型肌纤维组成的肌肉中，已经证明了低水平的CI-MPR。 小鼠模型的初步结果显示，β-2激动剂治疗增强了CI-MPR表达，并增加了GAA替代治疗的疗效，从而证实了CI-MPR在庞贝氏症替代治疗中的关键作用。 本申请提出了一项52周的安慰剂对照、双盲研究，在20名患有晚发性庞贝氏症的成年患者中使用β-2激动剂克仑特罗作为ERT的替代疗法。 本研究的具体目的1是确定克伦特罗作为预防治疗的安全性和有效性。初步评估将包括肌肉力量测试，6分钟步行 测试和肺功能测试。安全性评价将包括研究药物治疗期间的标准血液检查和心电图。本研究的具体目的2是确定克伦特罗治疗对患者受体介导的重组GAA摄取的影响。将评估克伦特罗对CI-MPR表达的影响。 将通过比较肌肉功能和基线和克伦特罗给药期间肌肉中糖原积累的生化校正来分析增强的CI-MPR介导的GAA摄取的影响。将监测尿生物标志物葡萄糖四氢叶酸（Glc 4）。正在进行这些研究，以确定生化校正和临床终点之间是否存在任何相关性。

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.