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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 摘要 假设 重组人酸性-α-葡萄糖苷酶（rhGAA）（也称为美而赞）的酶替代疗法在治疗起病型庞贝氏症患者中安全有效，可改善疾病的某些体征和症状。 具体目标 本方案的目的是在扩大使用的基础上，为无替代治疗且不符合Genzyme Corporation申办的其他目前入组的新发庞贝氏症患者的入选标准中描述的临床特征的新发庞贝氏症重度患者提供美而赞酶替代治疗。 背景和意义 庞贝氏症（也称为糖原累积病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，这是溶酶体糖原降解所必需的。庞贝氏症的特征在于受影响个体的许多身体组织中糖原的细胞器结合（溶酶体）积聚，这与大多数其他糖原储存障碍中发生的糖原的排他性胞质积聚相反。在患有典型疾病的婴儿的心肌和骨骼肌以及肝组织中，蓄积最显著。 GAA缺乏症的临床表现从迅速致命的婴儿疾病到经常与呼吸功能不全相关的缓慢进行性迟发性肌病不等。最严重的形式是典型的心脏病发作性疾病，其特征是显著的心脏肥大、张力减退、肝肿大和由于心肺衰竭而死亡，通常发生在2岁之前。较温和的庞贝氏症是一种缓慢进展的近端肌病性成人发病疾病，发病晚至第二至第六个十年，基本上只累及骨骼肌。在这两个极端之间有一个异质性组，不同地称为儿童，青少年或肌肉变异，通常在婴儿早期后发病，骨骼肌受累占主导地位，通常不涉及心脏，与经典的战斗中发病的庞贝氏症相比，进展过程更缓慢。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氏症的方法。姑息治疗和支持性护理是治疗的主要手段。酶替代疗法可以有效地减缓或逆转疾病的症状或将更严重的表型转化为更温和的表型。 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，具有用于在ER内合成的氨基末端信号序列。该酶通过ER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进行广泛的后修饰，提供了靶向溶酶体的甘露糖-6-磷酸识别标记物。该酶还通过氨基末端和C末端蛋白水解裂解（主要在溶酶体内）进行修饰。本研究的申办方Genzyme Corporation生产了用于酶替代疗法的重组人GAA（rhGAA）的高纯度制剂，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.