Teaching tolerance: New approaches to enzyme replacement therapy for Pompe disease
Volume 8, Issue 10
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Pages 1459 - 1464http://dx.doi.org/10.4161/hv.21405
: 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 View affiliations
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