title: Teaching tolerance: New approaches to enzyme replacement therapy for Pompe disease.
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.
authors.affiliation: EpiVax, Inc., Providence, RI, USA.
authors.forename: Leslie P
authors.initials: LP
authors.lastname: Cousens
authors.forename: Federico
authors.initials: F
authors.lastname: Mingozzi
authors.forename: Sander
authors.initials: S
authors.lastname: van der Marel
authors.forename: Yan
authors.initials: Y
authors.lastname: Su
authors.forename: Richard
authors.initials: R
authors.lastname: Garman
authors.forename: Valerie
authors.initials: V
authors.lastname: Ferreira
authors.forename: William
authors.initials: W
authors.lastname: Martin
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
authors.forename: Anne S
authors.initials: AS
authors.lastname: De Groot
mesh_terms: D056947:Enzyme Replacement Therapy / Q000379:methods*; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008247:Lysosomes / Q000201:enzymology; D008954:Models, Biological; D000520:alpha-Glucosidases / Q000276:immunology / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D000520:alpha-Glucosidases
keywords: ADA; Anti-drug Antibodies; ERT; Enzyme Replacement Therapy; Lysosomal acid alpha glucosidase (GAA); Pompe Disease; Regulatory T cell; Treg; Tregitope; tolerance