Gene therapy for preserving the visual system in lysosomal storage diseases

项目摘要 拟议研究的主要目的是评估AAV-100的安全性和有效性。 用于预防进行性视网膜和中枢神经系统（CNS）的介导的基因疗法 在CLN2神经元蜡样质脂褐质沉积症（NCL）的犬模型中的变性，特别是当它们 与功能性视觉有关。CLN2疾病由可溶性溶酶体酶缺乏引起 三肽基肽酶-1（TPP1）由TPP1突变引起。在基因组中有无效突变的腊肠 TPP1用于临床前研究，支持开发CNS酶替代品 ERT治疗（ERT）已成功地保留了受影响儿童的神经功能。 不幸的是，这种治疗不能防止视网膜变性或由此导致的失明， CLN2疾病此外，ERT治疗需要长期的临床基础脑室内 每隔一周注射一次使用狗模型，将进行研究以测试 假设联合一次性玻璃体内和脑脊液内施用AAV- TPP1基因治疗载体将预防视网膜变性和视觉中枢变性 的中枢神经系统和保护功能性视力，为测试这种治疗在儿童中的阶段 CLN2疾病

PROJECT SUMMARY The primary objective of the proposed research is to evaluate the safety and efficacy of AAV- mediated gene therapy for preventing the progressive retinal and central nervous system (CNS) degeneration in a canine model of CLN2 neuronal ceroid lipofuscinosis (NCL), particularly as they relate to functional vision. CLN2 disease results from deficiency of the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1) caused by mutations in TPP1. Dachshunds with a null mutation in TPP1 were used in preclinical studies that supported development of CNS enzyme replacement therapy (ERT) that has been successful in preserving neurological function in affected children. Unfortunately, this treatment does not prevent retinal degeneration or the resulting blindness in CLN2 disease. In addition, ERT treatments require long clinic-bases intracerebroventricular injections every other week for life. Using the dog model, studies will be conducted to test the hypothesis that combined one-time intravitreal and intra-cerebrospinal fluid administration of AAV- TPP1 gene therapy vectors will prevent retinal degeneration and degeneration of the visual centers of the CNS and preserve functional vision, setting the stage for testing this treatment in children with CLN2 disease.