AN OPEN - LABEL EXTENSION STUDY OF PATIENTS WITH LATE-ONSET POMPE DISEASE

晚发性庞贝病患者的开放标签扩展研究

• 批准号: 7953707
• 负责人: MELISSA P WASSERSTEIN
• 金额: $ 3.77万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7953707
• 关键词: 1 year old; 2 year old; Acids; Age; Alpha-glucosidase; Binding; Cardiac Death; Cardiomyopathies; Cessation of life; Childhood; Chinese Hamster Ovary Cell; Clinical; Clinical Course of Disease; Clinical Research; Clinical Trials; Code; Computer Retrieval of Information on Scientific Projects Database; DNA; Deposition; Deterioration; Development; Disease; Dissociation; Enrollment; Enzymes; Funding; Glycogen; Glycogen storage disease type II; Grant; Heart; Human; Individual; Inherited; Institution; Life; Literature; Metabolic; Molecular; Motor; Muscle; Muscle Weakness; Muscle function; Muscle hypotonia; Myopathy; Neurology; Newly Diagnosed; Observational Study; Organ; Pathology; Patients; Pediatrics; Pelvis; Recombinants; Research; Research Personnel; Resources; Respiratory Failure; Respiratory Muscles; Safety; Shoulder; Skeletal Muscle; Source; Symptoms; Time; United States National Institutes of Health; Ventilator; Wheelchairs; base; enzyme replacement therapy; experience; glucosidase; infancy; open label; prevent; programs; prospective; respiratory; skeletal

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. 9/18/2007 Pompe disease is a rare autosomal recessive metabolic muscle disease caused by the deficiency of acid ? 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; Lafor¿t, 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 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 (Lafor¿t, 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.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 2007年9月18日 庞贝疾病是由酸缺乏引起的一种罕见的常染色体隐性代谢肌肉疾病？葡萄糖酶（GAA），一种降解溶酶体糖原的酶。从历史上看，庞贝疾病已根据症状发作时的年龄，器官受累的程度和进展速度而被任意分为不同的亚型。从本质上讲，从快速进行的形式（婴儿发作）到更多的疾病，重要的是要注意，庞贝疾病的所有表现都具有共同的潜在病理学；即，GAA的缺乏，随后积累了糖原。 在疾病范围的最迅速进行的末端，是庞贝疾病基础设施形式的患者。这些患者通常在第一次出现症状 生命12个月。糖原在心脏和骨骼肌中的大规模沉积会导致迅速进行性心肌病和普遍性的肌肉无力和性肌张力。此外，通常会完全逮捕汽车的发展，或者如果实现了运动里程碑，则会丢失。心脏和/或呼吸衰竭的死亡通常发生在大多数患者达到1岁之前（Hirschhorn，2001年，是遗传疾病的代谢和分子碱基）。在文献中将出现这种典型疾病病程的患者描述为患有“经典”婴儿发作疾病。 Slonim及其同事描述了生存超过1年的婴儿发作庞贝疾病的一部分（Slonim，2000，J Pediatr）。这些患者的临床疾病过程的特征是心肌病的进展缓慢，生存期更长，患者通常在1至2岁之间出现呼吸衰竭。尽管有些患者在1岁之前死亡，但其他患者可能会超过2年。 庞贝疾病的后期形式的进展速度较快，而不是基础设施 - 发作形式。症状出现在童年时期或生命的第六个十年。患者患有进行性肌病，主要是骨盆和肩膀女孩的近端肌肉，以及呼吸受累的变化。通常，这些患者的心肌病很少或没有心肌病（Chen，2000，今天的Mol Med；Lafor¿t，2000，神经病学； Hirschhorn，Hirschhorn， 2001年，遗传疾病的代谢和分子碱基）。晚期的过程 Pompe disease is less predictable than the infantile form, with some patients experiencing a rapid definition in skeletal and respiratory muscle function leading to loss of ambulatory and respiratory failure, others progressing less rapidly, and yet others with dissociation in the progression of skeletal and respiratory definition in skeletal and respiratory muscle function leading to loss of ambulatory and respiratory failure, others progressing less rapidly, and yet others with dissociation in the progression of骨骼和呼吸道肌肉受累（Lafor回节，2000年，神经病学）。 最终，大多数患者成为轮椅结合，需要呼吸机的支撑，并最终屈服于呼吸衰竭（Chen，2000，Mol Med今天； Hirshhorn，2001年，遗传病的代谢和分子基础）。 Genzyme Corporation已经生产了一种重组形式的人酸α-葡萄糖苷酶（RHGAA），肌酶，这是一种用于蓬松疾病的研究酶替代疗法（ERT）。希望ERT能够恢复溶酶体GAA活性，复制的溶酶体糖原，并防止进一步的底物积累。 RHGAA由中国仓鼠卵巢细胞产生，为GAA编码的脱氧核糖核酸（cDNA）在其中稳定地表达。 婴儿发作形式的临床试验目前已关闭。目前，新诊断的婴儿发作患者可能会根据Genzyme扩大访问计划接受ERT。晚期发作的前瞻性观察研究（LOPOS）始于2004年，还被58名轻度至中间发作的庞贝疾病的人完全招募。开始对晚发病患者的临床足迹非常重要。 假设： 本研究旨在评估肌酶在晚发病患者中的安全性和效率。