MYOZYME TREATMENT IN PATIENTS WITH LATE ONSET POMPE DISEASE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。庞贝病是一种罕见的常染色体隐性代谢性肌肉疾病，由酸a葡萄糖苷酶（GAA）缺乏引起，GAA是一种降解溶酶体糖原的酶。历史上，庞贝病根据发病年龄、器官受累程度和进展至死亡的速度被随意地分为不同的亚型。从本质上讲，疾病的范围很广，从快速进展的形式（婴儿发病）到缓慢进展的形式（晚发病），这些极端之间存在相当大的可变性和重叠（Chen, 2000, Mol Med Today; Hirschhorn, 2001，遗传疾病的代谢和分子基础；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，随后糖原积累。在疾病谱系中进展最快的一端是患有婴儿期庞贝病的患者。这些患者通常在出生后的前12个月内出现症状。糖原在心脏和骨骼肌的大量沉积导致迅速进展的心肌病和全身性肌无力和肌张力低下。此外，运动发育经常完全停止，或者即使达到了运动里程碑，它们随后也会丢失。心脏和/或呼吸衰竭导致的死亡通常发生在大多数患者未满1岁之前（Hirschhorn, 2001，遗传疾病的代谢和分子基础）。出现这种典型病程的患者在文献中被描述为“经典”婴儿期发病的庞贝病。Slonim和他的同事曾报道过一组婴儿起病的庞贝病患者存活超过1年（Slonim, 2000, J pediatrics）。这些患者的临床病程特点是心肌病进展较慢，生存期较长，患者通常在1至2岁之间出现呼吸衰竭。虽然有些患者在1岁前死亡，但其他患者可能存活超过2年。迟发型庞贝病的进展速度不及婴儿期型庞贝病。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，主要是骨盆和肩带的近端肌肉，呼吸系统受累的变化进展。这些患者通常发展为轻微或无心肌病（Chen, 2000, Mol Med Today; LaforOt, 2000, Neurology; Hirschhorn, 2001，遗传疾病的代谢和分子基础）。迟发性庞贝病的病程比婴儿期更难以预测，一些患者会经历骨骼和呼吸肌功能的迅速恶化，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和呼吸肌受累的过程中出现分离（Lafort, 2000, Neurology）。最终，大多数患者被轮椅束缚，需要呼吸机支持，最终死于呼吸衰竭（Chen, 2000, Mol Med Today; Hirshhorn, 2001，遗传疾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，一种用于庞贝病的研究性酶替代疗法（ERT）。希望ERT能恢复溶酶体GAA活性，消耗积累的溶酶体糖原，防止底物进一步积累。rhGaa由中国仓鼠卵巢细胞产生，其中编码GAA的互补脱氧核糖核酸（cDNA）已稳定表达。婴儿发病形式的临床试验目前已停止登记。目前，新诊断的婴儿发病患者可以在健赞扩大准入计划下接受ERT。迟发性前瞻性观察研究（LOPOS）开始于2004年，也纳入了58例轻度至中度迟发性庞贝病患者。开展迟发性患者的临床试验具有重要意义。假设：本研究旨在评估Myozyme在迟发性庞贝病患者中的安全性和有效性。

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 (Lafort, 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.