Inducing Tolerance to Enzyme Replacement Therapy for Pompe Disease Pompe disease is a lysosomal storage disorder caused by defects in the enzyme acid alpha-glucosidase (GAA) that leads to glycogen accumulation affecting heart and skeletal muscle. Enzyme-replacement therapy with recombinant human (rh)GAA saves the lives of children with Pompe disease. The prognosis for patients who have no circulating endogenous GAA (CRIM-negative Pompe disease) is markedly worse. The development of high titers of anti-rhGAA antibody and decreased effectiveness of replacement therapy often result in the death of CRIM-negative Pompe infants in the first year of life. We propose to evaluate the effect of natural tolerance-inducing peptides, Tregitopes, in a murine model of CRIM-negative Pompe disease. Tregitopes cause the expansion and activation of regulatory T cells, suppress inflammatory T cell responses and reduce humoral immune responses to co-administered proteins. In the plan outlined here, we will test Tregitopes co-delivered with GAA epitopes, as a tolerance-inducing (1) Prophylactic therapy or (2) Therapeutic treatment of ongoing anti-GAA immune responses. We will evaluate an AAV-vector for Tregitope-GAA epitope delivery. The program will establish proof-of-principle that will lead to further studies in Phase II. Even a moderate degree of success with the protocol developed here may improve the lives of CRIM-negative babies and could be applied to other enzyme replacement therapies to which ADA have been induced. An experienced team will carry out the program, including Richard Garman who has extensive experience with the Pompe mouse model, Annie De Groot, a well-established T cell immunologist, Leslie Cousens, Ph.D. expert in Tregitope immunomodulation studies, Tim Messitt, Ph.D. molecular biologist and Federico Mingozzi Ph.D., AAV expert, who will co-develop the Tregitope-GAA AAV vector.
NIH ExPorter
NIH ExPorter