MYOZYME TREATMENT IN PATIENTS WITH LATE ONSET POMPE DISEASE

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 is a rare autosomal recessive metabolic muscle disease caused by the deficiency of acid a 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; LaforOt, 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 muscle involvement (Lafort, 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.