EXPANDED ACCESS USE OF RECOMBINANT HUMAN ACID ALPHA-GLUCOSIDASE (RHGAA) (MYOZ

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。 摘要 假设 重组人酸-α-葡萄糖苷酶(RhGAA)，也称为Myozyme，对婴儿起病的庞贝病患者进行酶替代治疗，在改善疾病的一些体征和症状方面是安全有效的。 具体目标 该协议的目的是在扩大准入的基础上，为那些没有替代治疗方法并且不符合Genzyme公司赞助的其他研究的纳入标准中描述的临床特征的婴儿发作性庞贝病患者提供Myozyme的酶替代疗法。 背景和意义 Pompe病(又称糖原储存病II型，GSD-II，或酸性麦芽糖酶缺乏症，AMD)是一种罕见的常染色体隐性遗传病，由酸性α-葡萄糖苷酶(GAA)缺乏引起，酸性α-葡萄糖苷酶是溶酶体糖原降解所必需的。Pompe病的特征是细胞器结合(溶酶体)的糖原在患者体内的许多组织中积聚，而不是大多数其他糖原储存障碍中发生的独占的细胞质糖原积聚。这种积聚在心肌和骨骼肌以及患有经典疾病的婴儿的肝脏组织中最为明显。 GAA缺乏症的临床表现从一种迅速致命的婴儿疾病到一种缓慢进展的迟发性肌病，通常与呼吸功能不全有关。最严重的形式是典型的婴儿发病疾病，其特征是明显的心脏增大、低张、肝脏增大，以及通常在2岁之前死于心肺衰竭。Pompe病较轻的变种是一种进展缓慢的近端肌病，成人起病，发病晚至第二到六十年，基本上只累及骨骼肌。在这两个极端之间，有一个不同的组，不同的名称，不同的儿童期，青少年，或肌肉变异体，通常在婴儿早期起病，骨骼肌受累为主，通常没有心脏受累，与典型的婴儿起病的庞培病相比，进展更慢。进行性近端肌肉无力，包括呼吸功能的严重损害，占主导地位，死亡通常由呼吸衰竭引起。 目前还没有得到批准的有效治疗庞培病的方法。姑息性和支持性护理是管理的支柱。酶替代疗法可能在减缓或逆转疾病症状或将较严重的表型转变为较轻的表型方面有效。 人酸性α-葡萄糖苷酶是一种非糖基化蛋白质，含有952个氨基酸，在内质网内合成有一个氨基端信号序列。该酶在翻译后被广泛修饰，通过内质网内的糖基化、天冬酰胺连接的碳水化合物的重塑和甘露糖残基的磷酸化，为靶向溶酶体提供甘露糖-6-磷酸识别标记。该酶还被氨基和C末端的蛋白水解性切割所修饰，主要是在溶酶体中。这项研究的赞助商Genzyme公司生产了一种用于酶替代治疗的高度纯化的重组人GAA(RhGAA)制剂，称为Myozyme。

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. ABSTRACT HYPOTHESIS Enzyme replacement therapy with recombinant human acid-alpha-glucosidase (rhGAA), also called Myozyme, in patients with infantile-onset Pompe Disease is safe and effective in ameliorating some signs and symptoms of the disease. SPECIFIC AIMS The objective of this protocol is to provide enzyme replacement therapy with Myozyme, on an expanded access basis, to severely affected patients with infantile-onset Pompe disease for whom there is no alternative treatment and who do not meet the clinical characteristics described in the inclusion criteria of other Genzyme Corporation-sponsored studies currently enrolling patients with infantile-onset Pompe disease. BACKGROUND AND SIGNIFICANCE Pompe disease (also called glycogen storage disease type II, GSD-II, or acid-maltase deficiency, AMD) is a rare autosomal recessive disease caused by the deficiency of acid alpha-glucosidase (GAA), which is needed for the degradation of lysosomal glycogen. Pompe disease is characterized by organelle bound (lysosomal) accumulation of glycogen in many body tissues of affected individuals, as opposed to the exclusive cytoplasmic accumulation of glycogen that occurs in most other glycogen storage disorders. The accumulation is most marked in cardiac and skeletal muscle and in hepatic tissues of infants with the classical disorder. Clinical presentation of GAA deficiency ranges from a rapidly fatal infantile disease to a slowly progressive late-onset myopathy frequently associated with respiratory insufficiency. The most severe form is the classic infantile-onset disease characterized by prominent cardiomegaly, hypotonia, hepatomegaly, and death due to cardiorespiratory failure, usually before 2 years of age. The milder variant of Pompe disease is a slowly progressive proximal myopathic adult-onset disease with onset as late as the second to sixth decade and involvement essentially only of skeletal muscle. Between these two extremes there is a heterogeneous group, variously termed childhood, juvenile, or muscular variant, generally with onset after early infancy, a predominance of skeletal muscle involvement, usually without cardiac involvement, and a more slowly progressive course as compared with classic infantile-onset Pompe disease. Progressive proximal muscle weakness including major impairment of respiratory function dominates the picture and death results usually from respiratory failure. There is currently no approved, effective treatment for Pompe disease. Palliative and supportive care provides the mainstay of management. Enzyme replacement therapy may be effective in slowing or reversing symptoms of the disease or converting a more severe phenotype into a milder phenotype. Human acid alpha glucosidase is a nonglycosylated protein containing 952 amino acids with an amino-terminal signal sequence for synthesis within the ER. The enzyme is extensively modified posttranslationally by glycosylation within the ER with remodeling of the asparagine-linked carbohydrate and phosphorylation of mannose residues, providing the mannose-6-phosphate recognition marker for targeting to lysosomes. The enzyme is additionally modified by both amino- and C-terminal proteolytic cleavage, primarily within lysosomes. The sponsor of this study, Genzyme Corporation, has produced a highly purified preparation of recombinant human GAA (rhGAA) for enzyme replacement therapy, termed Myozyme.