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

庞贝病(糖原贮积症II型；酸性麦芽糖酶缺乏症；MIM 232300)是一种肌病，类似于晚发的四肢带状肌营养不良症 形式，这是由于酸性α-葡萄糖苷酶(GAA)缺乏造成的条纹和 平滑的肌肉。重组人的酶替代疗法(ERT) (Rh)GAA在很大程度上使疾病进程从 迟发性庞贝病的肺和运动透视。溶酶体 储存障碍，如庞贝病，可以更有效地治疗，如果 阳离子非依赖性甘露糖-6-磷酸受体(CI-MPR)摄取障碍 可以清除。成年哺乳动物肌肉中CI-MPR的缺乏 强调CI-MPR限制了庞贝病ERT的概念。 以前，在GAAKO的骨骼肌中显示出低水平的CI-MPR 小鼠，特别是主要由II型肌纤维组成的肌肉。我们的 初步结果显示，b2受体激动剂治疗可增强CI-MPR。 GAA替代疗法的表达和提高疗效，从而 确认CI-MPR在庞培病替代治疗中的关键作用 疾病。目前，我们计划在患者身上进行b2-激动剂治疗的试点临床试验。 在急诊室接受了迟发性庞贝病的治疗。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。 安全性评估将包括标准的血液测试和心电图， 在研究药物的时候。患者将在整个急救过程中继续接受标准护理 审判。这项研究将在杜克大学医院系统进行， 由调查员发起的对杜克大学机构审查委员会的审查。

Pompe disease (Glycogen storage disease type II; acid maltase deficiency; MIM 232300) is a myopathy, similar to limb-girdle muscular dystrophy in its late-onset form, which results from acid a-glucosidase (GAA) deficiency in striated and smooth muscle. Enzyme replacement therapy (ERT) with recombinant human (rh) GAA has largely resulted in stabilization of the disease process from a pulmonary and motor perspective in late-onset Pompe disease. Lysosomal storage disorders such as Pompe disease can 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. Previously, low levels of CI-MPR were demonstrated in skeletal muscle of GAAKO mice, specifically in muscles comprised primarily of type II myofibers. Our preliminary results revealed that b2-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. Currently we plan a pilot clinical trial of b2-agonist therapy in patients with late-onset Pompe disease on ERT. The 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. Patients will continue on standard of care ERT throughout the trial. The study will be conducted at Duke University Hospital System with the review of the Duke Institutional Review Board under an investigator initiated IND.