Inducing Tolerance to Enzyme Replacement Therapy for Pompe Disease

描述（由申请方提供）：诱导庞贝氏症对酶替代疗法的耐受性庞贝氏症是一种溶酶体贮积症，由酸性α-葡萄糖苷酶（GAA）缺陷引起，导致影响心脏和骨骼肌的糖原蓄积。重组人（rh）GAA的酶替代疗法可挽救庞贝氏症儿童的生命。没有循环内源性GAA（CRIM阴性庞贝氏症）的患者的预后明显更差。高滴度抗rhGAA抗体的产生和替代治疗有效性的降低通常导致CRIM阴性庞贝氏症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CRIM阴性庞贝氏症小鼠模型中的作用。Tregitope引起调节性T细胞的扩增和活化，抑制炎性T细胞应答并降低对共同施用的蛋白质的体液免疫应答。在这里概述的计划中，我们将测试与GAA表位共同递送的Tregitopes，作为正在进行的抗GAA免疫应答的耐受诱导（1）预防性治疗或（2）治疗性治疗。我们将评估用于Tregitope-GAA表位递送的AAV载体。该计划将建立原理证明，这将导致在第二阶段的进一步研究。即使是在这里开发的协议的中等程度的成功可能会改善CRIM阴性婴儿的生活，并可以应用于其他酶替代疗法，ADA已被诱导。一个经验丰富的团队将执行该计划，包括在Pompe小鼠模型方面拥有丰富经验的Richard Garman，成熟的T细胞免疫学家Annie De Groot，Leslie Cousens博士。Tregitope免疫调节研究专家Tim Messitt博士分子生物学家和费德里科·明戈齐博士，AAV专家，他将共同开发Tregitope-GAA AAV载体。 公共卫生相关性：我们建议评估天然耐受诱导肽Tregitopes（T调节细胞表位）在庞贝氏症小鼠模型中诱导对酶替代疗法的持久和特异性耐受的效果。Tregitopes在庞贝氏症背景下治疗抗药抗体反应的原理证明将对酶替代疗法领域产生直接影响，并可能导致Tregitope疗法在这些儿童治疗中的加速适应。

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.