Commentary

Teaching tolerance: New approaches to enzyme replacement therapy for Pompe disease

Volume 8, Issue 10   October 2012
Pages 1459 - 1464
http://dx.doi.org/10.4161/hv.21405
Keywords: ADA, Anti-drug Antibodies, ERT, Enzyme Replacement Therapy, Lysosomal acid alpha glucosidase (GAA), Pompe Disease, Regulatory T cell, Treg, Tregitope, tolerance
Authors: Leslie P. Cousens, Federico Mingozzi, Sander van der Marel, Yan Su, Richard Garman, Valerie Ferreira, William Martin, David W. Scott and Anne S. De Groot

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Abstract:
Babies born with Pompe disease require life-long treatment with enzyme-replacement therapy (ERT). Despite the human origin of the therapy, recombinant human lysosomal acid α glucosidase (GAA, rhGAA), ERT unfortunately leads to the development of high titers of anti-rhGAA antibody, decreased effectiveness of ERT, and a fatal outcome for a significant number of children who have Pompe disease. The severity of disease, anti-drug antibody (ADA) development, and the consequences thereof are directly related to the degree of the enzyme deficiency. Babies born with a complete deficiency GAA are said to have cross-reactive immunologic material (CRIM)–negative Pompe disease and are highly likely to develop GAA ADA. Less frequently, GAA ADA develop in CRIM-positive individuals. Currently, GAA-ADA sero-positive babies are treated with a combination of immunosuppressive drugs to induce immunological tolerance to ERT, but the long-term effect of these regimens is unknown. Alternative approaches that might redirect the immune response toward antigen-specific tolerance without immunosuppressive agents are needed. Methods leading to the induction of antigen-specific regulatory T cells (Tregs), using peptides such as Tregitopes (T regulatory cell epitopes) are under consideration for the future treatment of CRIM-negative Pompe disease. Tregitopes are natural T cell epitopes derived from immunoglobulin G (IgG) that cause the expansion and activation of regulatory T cells (Treg). Teaching the immune system to tolerate GAA by co-delivering GAA with Tregitope peptides might dramatically improve the lives of CRIM-negative babies and could be applied to other enzyme replacement therapies to which ADA have been induced.

Received: June 29, 2012; Accepted: July 7, 2012; Published Online: October 1, 2012

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