The role of immune tolerance induction in restoration of the efficacy of ERT in Pompe disease§

Authors

  • Emanuela Lacaná,

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    • Emanuela Lacaná, Ph.D., a team leader in the Division of Therapeutic Protein, Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration in Bethesda, MD. Her scientific interests focus on the review and advancement of product quality for biotechnology-based rare disease drugs.

  • Lynne P. Yao,

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    • Lynne P. Yao, M.D. is currently a clinical team leader in the Division of Gastroenterology and Inborn Errors Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD. Her scientific interests have centered on the review and clinical development of drugs and biologic products used to treat rare, inherited metabolic diseases.

  • Anne R. Pariser,

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    • Anne R. Pariser, M.D. is the Associate Director for Rare Diseases in the Office of New Drugs at the U.S. Food and Drug Administration's Center for Drug Evaluation and Research in Silver Spring, MD. Her scientific interests focus on advancing research into rare diseases and the clinical development of drug and biological products to used to treat these disorders.

  • Amy S. Rosenberg

    Corresponding author
    • Office of Pharmaceutical Science, Office of Biotechnology Products, Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892.
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    • Amy S. Rosenberg, M.D. is the Director of the Division of Therapeutic Proteins in the Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Her scientific interests encompass immune tolerance induction in the setting of transplantation, autoimmunity, and therapeutic protein administration.


  • Emanuela Lacaná and Lynne P. Yao contributed equally to this study.

  • The views expressed in this article represent the opinions of the authors and do not necessarily represent the policy of the US Food and Drug Administration.

  • §

    The authors have indicated they have no financial relationships relevant to this article to disclose.

  • How to cite this article: Lacaná E, Yao LP, Pariser AR, Rosenberg AS. 2012. The role of immune tolerance induction in restoration of the efficacy of ERT in Pompe disease. Am J Med Genet Part C Semin Med Genet 160C:30–39.

Abstract

Pompe disease is a lysosomal storage disorder caused by deficiency in the enzyme acid α-glucosidase (GAA). Pompe disease is characterized by the accumulation of glycogen, predominantly in muscle tissue, leading to progressive muscle weakness, loss of motor, respiratory, and, in the infantile-onset form, cardiac function. Disease progression is highly variable depending on phenotype, but premature death due to respiratory complications occurs in most patients. Beginning in 2006, approved alglucosidase alfa enzyme replacement therapies [recombinant human (rh) GAA] have been available to treat Pompe patients. Treatment of classic infantile-onset patients, who manifest the severest form of the disease, with alglucosidase alfa (Myozyme®) has led to extended survival and an evolving understanding of the pathophysiology and course of the disease. Moreover, such treatment has brought to light the role of the immune response in abrogating the efficacy of rhGAA in classic infantile-onset patients with severe genetic mutations. Thus, optimization of treatment for such patients includes development and utilization of strategies to prevent or eliminate immune responses, including modulating the immune system (prophylactic and therapeutic immune tolerance induction regimens) and engineering the enzyme to be less immunogenic and more effective. Future research is also critical for evaluating and mitigating novel disease-associated pathologies uncovered by prolonged survival of infantile-onset patients including development of novel therapeutics, and for protein design strategies to increase delivery of enzyme replacement therapy to critical target tissues. Such efforts would be greatly bolstered by further development of predictive animal models and biomarkers to facilitate clinical trials and patient management. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

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