Developments in the Treatment of Pompe Disease

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Citation
US Cardiology, 2006;3(2):1-4

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Overview

Pompe disease, also known as glycogen storage disease type II or acid maltase deficiency, is a rare, debilitating, and often fatal lysosomal storage disease. It is caused by an autosomal recessively inherited deficiency of the enzyme acid ╬▒-glucosidase (GAA) that hydrolyzes glycogen to glucose in the lysosome; the deficiency causes the deposition of glycogen in multiple tissues, predominantly skeletal, smooth, and cardiac muscle. The age of onset and the symptoms vary considerably.1 All patients experience considerable morbidity and often early mortality, particularly in infantile onset Pompe disease. Until recently, the natural history of infantile onset Pompe disease was uniformly poor with death occurring usually by one year of age from cardiomyopathy or respiratory failure. Clinical management thereby consisted solely of palliative care.2,5

Myozyme® (alglucosidase-α, Genzyme, Cambridge MA) has recently been approved for use for the treatment of Pompe disease.3 Enzyme replacement therapy with Myozyme has been demonstrated to improve overall survival and ventilator-free survival, reverse cardiomyopathy and improve motor development in infants with Pompe disease.4 Myozyme is the first approved treatment for the to 10,000 children and adults currently affected by Pompe disease.

Description of the Compound

Myozyme consists of the human enzyme acid ╬▒-glucosidase (rhGAA) produced by recombinant DNA technology in a Chinese hamster ovary cell line. It degrades glycogen by catalyzing the hydrolysis of alpha 1, 4 and alpha 1, 6 glycosidic linkages of lysosomal glycogen. Myozyme is a glycoprotein with a calculated mass of 99,377 daltons for the polypeptide chain with a total mass of approximately 109,000 daltons. It is infused intravenously and is supplied as a sterile, nonpyrogenic, white, lyophilized powder for reconstitution with 10.3ml sterile water for injection.3

Myozyme provides an exogenous source of GAA. It binds to mannose-6-phosphate receptors on the cell surface via the carbohydrate groups on the molecule. It is subsequently internalized and transported into lysosomes where it undergoes proteolytic cleavage to its mature form resulting in increased enzymatic activity able to cleave glycogen.3

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References
  1. Hirschhorn R, Reuser AJ, Glycogen storage disease type II: acid a-glucosidase (acid maltase) deficiency , in Scriver CR, Beudet AL, Sly WS, et al. (eds), The Metabolic and Molecular Basis of Inherited Disease (2001), New York: McGraw-Hill, pp. 3389-3420.
  2. Van den Hout HM, Hop W, van Diggelen OP, et al., The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literature , Pediatrics (2003);112: pp. 332-340.
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  3. http://www.myozyme.com
  4. Kishnani PS, Corzo D, Nicolino M, et al., Recombinant human acid a-glucosidase: major clinical benefits in infantile onset Pompe disease , Neurology (2007), in press.
  5. Kishnani PS, Hwu WL, Mander H, et al., A retrospective, multinational, multicenter study on the natural history of infantileonset Pompe disease , J Pediatrics (2006);148: pp. 671-676.
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  7. Kishnani PS, Nicolino M, Voit T, et al., Chinese hamster ovary cell-derived recombinant human acid alpha-glucosidase in infantile-onset Pompe disease , J Pediatr (2006);149: pp. 89-97.
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  8. Raben N, Fukuda T, Gilbert AL, et al., Replacing acid alpha-glucosidase in Pompe disease: recombinant and transgenic enzymes are equipotent, but neither completely clears glycogen from type II muscle fibers , Mol Ther (2005);11: pp. 48-56.
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  11. Ansong AK, Li JS, Grayck EN, et al., Electrocardiographic changes in Pompe disease following enzyme replacement therapy , Genet Med (2006);8: pp. 297-301.
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  12. Ing RJ, Cook DR, Bengur AR, et al., Anesthetic management of infants with glycogen storage disease type II: a physiologic approach , Paediatr Anaesth (2004);14: pp. 514-519.
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  13. Cook AL, Kishnani PS, Carboni MP, et al., Ambulatory electrocardiogram analysis in infants with Pompe disease treated with enzyme replacement therapy , Genet Med (2006);8: pp. 313-317.
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  14. Kishnani PS, Steiner RD, Bali D, et al., Pompe disease diagnosis and management guideline , Genet Med (2006);8: pp. 267-288.
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