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

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。Pompe病（也称为糖原储存病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，GAA是降解溶酶体糖原所必需的。庞贝病的特点是受影响个体的许多身体组织中糖原的细胞器结合（溶酶体）积累，而不是在大多数其他糖原储存疾病中发生的糖原的细胞质积累。典型疾病婴儿的心脏、骨骼肌和肝组织中积聚最为明显。GAA缺乏症的临床表现从迅速致命的婴儿疾病到缓慢进展的迟发性肌病，通常伴有呼吸功能不全。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肿大、低张力、肝肿大和因心肺衰竭而死亡，通常发生在2岁之前。Pompe病的较轻变体是一种缓慢进展的近端肌病，发病晚至20至60岁，主要仅累及骨骼肌。介于这两种极端之间的是异质组，被称为儿童期、青少年期或肌肉型变异型，通常在婴儿期早期发病，主要累及骨骼肌，通常不累及心脏，与典型的婴儿期发病的庞贝病相比，病程进展较慢。进行性近端肌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。目前还没有批准的有效治疗庞贝病的方法。姑息治疗和支持性护理是治疗的主要内容。酶替代疗法可有效减缓或逆转疾病的症状，或将较严重的表型转化为较温和的表型。人α -葡萄糖苷酶是一种含有952个氨基酸的非糖基化蛋白，其氨基末端信号序列在内质网内合成。该酶在翻译后通过内质网内的糖基化进行广泛修饰，包括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-磷酸识别标记物。该酶主要在溶酶体内被氨基端和c端蛋白水解裂解所修饰。本研究的赞助商Genzyme公司生产了一种用于酶替代治疗的高纯度重组人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. 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 careprovides 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 thisstudy, Genzyme Corporation, has produced a highly purified preparation of recombinant human GAA (rhGAA) for enzyme replacement therapy, termed Myozyme.