SAFETY, EFFICACY & PHARMACOKINETICS OF MYOZYME IN PATIENTS WITH POMPE DISEASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 Pompe病是一种罕见的常染色体隐性代谢性肌肉疾病，由酸性a葡萄糖苷酶(GAA)缺乏引起，GAA是一种降解溶酶体糖原的酶。从历史上看，庞贝病根据出现症状的年龄、器官受累的程度和进展至死亡的比率被任意分为不同的亚型。从本质上讲，疾病的范围很广，从快速进展的形式(婴儿发病)到进展较慢的形式(晚发)，这些极端之间存在相当大的变异性和重叠(Chen，2000，Mol Med Today；Hirschhorn，2001，The Metoxic and Molectoral Bases of遗传病；van den Hout，2003，儿科)。值得注意的是，庞贝病的所有表现都有一个共同的潜在病理：即GAA缺乏并随后糖原积聚。 在疾病谱中进展最快的是婴儿起病形式的庞培病患者。这些患者通常在第一个月出现症状 12个月的生命。心肌和骨骼肌中糖原的大量沉积导致快速进展性心肌病和全身性肌肉无力和低张力。此外，运动的发展往往完全停滞，或者如果运动的里程碑被实现，它们随后就会丢失。心脏和/或呼吸衰竭的死亡通常发生在大多数患者1岁之前(赫希霍恩，2001，遗传病的代谢和分子基础)。在文献中，出现这种典型病程的患者被描述为典型的婴儿起病庞贝病。SLonim和他的同事已经描述了存活超过1年的婴儿起病的庞贝病患者的一个子集(SLonim，2000，J Pediatr)。这些患者的临床病程的特点是心肌病进展较慢，生存时间较长，患者通常在1至2岁之间发展为呼吸衰竭。虽然一些患者在1岁之前死亡，但另一些患者可能会存活2年以上。 迟发性庞培病的进展速度慢于婴儿起病的形式。症状出现在儿童时期，或晚至生命的第六个十年。患者表现为进行性肌病，主要发生在骨盆和肩带的近端肌肉，并有不同程度的呼吸受累进展。这些患者通常发展为轻微或无心肌病(Chen，2000，Mol Med Today；LaforOt，2000，Neuroology；Hirschhorn，2001，《遗传病的代谢和分子基础》)。迟发性庞培病的病程比婴儿期更难预测，一些患者的骨骼肌和呼吸肌功能迅速恶化，导致行走能力丧失和呼吸衰竭，另一些患者进展较慢，还有一些患者在骨骼肌和呼吸肌受累的进展中出现分离(LaforOt，2000，Neuroology)。 最终，大多数患者会坐在轮椅上，需要呼吸机支持，最终死于呼吸衰竭(Chen，2000，Mol Med Today；Hirshhorn，2001，《遗传病的代谢和分子基础》)。 Genzyme公司生产了一种重组形式的人酸性α-葡萄糖苷酶(RhGAA)，Myozyme，一种治疗庞贝病的研究用酶替代疗法(ERT)。人们希望ERT能恢复溶酶体GAA的活性，耗尽累积的溶酶体糖原，防止底物进一步堆积。中国仓鼠卵巢细胞中稳定表达了编码GAA的互补脱氧核糖核酸(CDNAs)。 婴儿发病形式的临床试验目前已关闭登记。目前，新诊断的婴儿发病患者可以根据Genzyme的Expanded Access计划接受ERT。晚发性前瞻性观察性研究(LOPOS)始于2004年，也完全纳入了58名轻至中度晚发性庞贝病患者。开展晚发患者的临床试验具有重要意义。 假设： 本研究旨在评价Myozyme治疗晚发性庞贝病的安全性和有效性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Pompe disease is a rare autosomal recessive metabolic muscle disease caused by the deficiency of acid a glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Historically, Pompe disease has been arbitrarily classified into different subtypes based on the age at onset of symptoms, extent of organ involvement, and rate of progression to death. Essentially, there is a broad spectrum of disease ranging from a rapidly progressive form (infantile-onset) to a more slowly progressive form (late-onset) with considerable variability and overlap existing between these extremes (Chen, 2000, Mol Med Today; Hirschhorn, 2001, The Metabolic and Molecular Bases of Inherited Disease; van den Hout, 2003, Pediatrics). It is important to note that all presentations of Pompe disease share a common underlying pathology; i.e., deficiency of GAA with subsequent accumulation of glycogen. At the most rapidly progressive end of the disease spectrum are patients with the infantile-onset form of Pompe disease. These patients typically present with symptoms within the first 12 months of life. A massive deposition of glycogen in the heart and skeletal muscle results in rapidly progressive cardiomyopathy and generalized muscle weakness and hypotonia. Moreover, motor development is often completely arrested, or if motor milestones are achieved, they are subsequently lost. Death from cardiac and/or respiratory failure generally occurs before most patients reach 1 year of age (Hirschhorn, 2001, The Metabolic and Molecular Bases of Inherited Disease). Patients presenting with this typical disease course have been described in the literature as having 'classical' infantile-onset Pompe disease. A subset of patients with infantile-onset Pompe disease that survive beyond 1 year has been described by Slonim and colleagues (Slonim, 2000, J Pediatr). The clinical course of disease in these patients is characterized by a slower progression of cardiomyopathy and longer survival, with patients generally developing respiratory failure between 1 and 2 years of age. Although some patients die before 1 year of age, others may survive beyond 2 years. The late-onset form of Pompe disease progresses less rapidly than the infantile-onset form. Symptoms appear during childhood or as late as the sixth decade of life. Patients present with progressive myopathy, predominantly of the proximal muscles in the pelvic and shoulder girdles, and a variable progression of respiratory involvement. Typically these patients develop minimal or no cardiomyopathy (Chen, 2000, Mol Med Today; LaforOt, 2000, Neurology; Hirschhorn, 2001, The Metabolic and Molecular Bases of Inherited Disease). The course of late-onset Pompe disease is less predictable than the infantile form, with some patients experiencing a rapid deterioration in skeletal and respiratory muscle function leading to loss of ambulation and respiratory failure, others progressing less rapidly, and yet others with dissociation in the progression of skeletal and respiratory muscle involvement (LaforOt, 2000, Neurology). Eventually, most patients become wheelchair-bound, require ventilator support and ultimately succumb to respiratory failure (Chen, 2000, Mol Med Today; Hirshhorn, 2001, The Metabolic and Molecular Bases of Inherited Disease). Genzyme Corporation has manufactured a recombinant form of human acid alpha-glucosidase, (rhGAA), Myozyme, an investigational enzyme replacement therapy (ERT) for Pompe disease. It is hoped that ERT will restore lysosomal GAA activity, deplete accumulated lysosomal glycogen, and prevent further substrate accumulation. The rhGaa is produced from Chinese hamster ovary cells into which the complementary deoxyribonucleic acid (cDNA) coding for GAA has been stably expressed. Clinical trials for infantile onset form are currently closed to enrollment. At the present time, newly diagnosed infantile onset patients may receive ERT under the expanded access program by Genzyme. Late-onset Prospective Observational Study (LOPOS) began in 2004 and is also fully enrolled with 58 individuals with mild to intermediate late-onset Pompe Disease. It is of much importance to begin the clinical trails on late-onset patients. Hypothesis: The present study intends to evaluate the safety and efficacy of Myozyme in patients with late-onset Pompe disease.