Inducing Tolerance to Enzyme Replacement Therapy for Pompe Disease

描述(申请人提供)：诱导对酶替代疗法的耐受性庞培病是一种溶酶体储存障碍，由酶酸性α-葡萄糖苷酶(GAA)缺陷引起，导致糖原积累，影响心脏和骨骼肌。重组人(Rh)GAA的酶替代疗法挽救了庞贝病儿童的生命。无循环内源性GAA(CRIM阴性庞贝病)的患者预后明显较差。高滴度的抗rhGAA抗体的产生和替代治疗效果的降低通常会导致CRIM阴性的庞贝婴儿在出生后一年内死亡。我们建议评估天然耐受诱导肽Tregitope在CRIM阴性庞贝病小鼠模型中的效果。三位表位导致调节性T细胞的扩张和激活，抑制炎性T细胞反应，并降低对联合给药蛋白的体液免疫反应。在这里概述的计划中，我们将测试与GAA表位共同传递的三个表位，作为诱导耐受的(1)预防性治疗或(2)正在进行的抗GAA免疫反应的治疗性治疗。我们将评估一种用于Tregitope-GAA表位传递的AAV载体。该计划将建立原则证明，这将导致第二阶段的进一步研究。即使这里开发的方案取得了一定程度的成功，也可能会改善CRIM阴性婴儿的生命，并可能应用于其他已诱导ADA的酶替代疗法。 公共卫生相关性：我们建议评估天然耐受诱导肽Tregitope(T调节细胞表位)在Pompe病小鼠模型中诱导对酶替代疗法的长期和特异性耐受的效果。证明Tregitope在庞贝病背景下治疗抗药抗体反应的原则将对酶替代疗法领域产生直接影响，并可能导致Tregitope疗法在这些儿童的治疗中加速适应。

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. PUBLIC HEALTH RELEVANCE: We propose to evaluate the effect of natural tolerance-inducing peptides, Tregitopes (T regulatory cell epitopes), to induce long-lasting and specific tolerance to enzyme replacement therapy in a murine model of Pompe disease. Proof of principle for Tregitopes in treating anti-drug antibody responses in the context of Pompe disease will have immediate impact on the field of enzyme replacement therapy and could lead to accelerated adaptation of Tregitope therapy in the treatment of these children.