This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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