Inducing Tolerance to Enzyme Replacement Therapy for Pompe Disease

描述（由申请人提供）：诱导对庞贝病酶替代疗法的耐受性庞贝病是一种溶酶体贮积障碍，由酸性α -葡萄糖苷酶（GAA）缺陷引起，导致糖原积聚影响心脏和骨骼肌。重组人（rh）GAA酶替代疗法挽救了庞贝病儿童的生命。无循环内源性GAA （crim阴性Pompe病）的患者预后明显更差。抗rhgaa抗体高滴度的发展和替代治疗有效性的降低通常导致crim阴性Pompe婴儿在出生后第一年死亡。我们建议评估天然耐受诱导肽Tregitopes在小鼠crim阴性Pompe病模型中的作用。tregiopes引起调节性T细胞的扩增和激活，抑制炎症T细胞反应，减少对共同给药蛋白的体液免疫反应。在这里概述的计划中，我们将测试Tregitopes与GAA表位共同递送，作为耐受诱导(1)预防性治疗或(2)持续抗GAA免疫反应的治疗性治疗。我们将评估用于Tregitope-GAA表位传递的aav载体。该项目将建立原理验证，从而在第二阶段进行进一步研究。即使在此开发的方案中取得中等程度的成功，也可能改善crim阴性婴儿的生活，并可应用于ADA诱导的其他酶替代疗法。一个经验丰富的团队将执行该计划，包括Richard Garman，他在Pompe小鼠模型方面拥有丰富的经验，Annie De Groot，一位知名的T细胞免疫学家，Leslie Cousens博士，Tregitope免疫调节研究专家，Tim Messitt博士，分子生物学家和Federico Mingozzi博士，AAV专家，他们将共同开发Tregitope- gaa AAV载体。

DESCRIPTION (provided by applicant): 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.