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Hum Vaccin Immunother. 2012 Oct;8(10):1459-64. doi: 10.4161/hv.21405. Epub 2012 Oct 1.

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

Author information

  • 1EpiVax, Inc., Providence, RI, USA.

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 Ī± 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.

KEYWORDS:

ADA; Anti-drug Antibodies; ERT; Enzyme Replacement Therapy; Lysosomal acid alpha glucosidase (GAA); Pompe Disease; Regulatory T cell; Treg; Tregitope; tolerance

PMID:
23095864
[PubMed - indexed for MEDLINE]
PMCID:
PMC3660767
Free PMC Article
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