Gene therapy for preserving the visual system in lysosomal storage diseases

项目总结 拟议研究的主要目标是评估AAV的安全性和有效性- 预防进展性视网膜和中枢神经系统(CNS)的基因治疗 CLN2型神经元性蜡样脂褐素沉着症(NCL)犬模型的变性 与功能视觉有关。CLN2病是由于可溶性溶酶体酶缺乏所致 三肽基肽酶-1(TPP1)基因突变所致。带有零突变的腊肠 TPP1用于支持开发CNS酶替代品的临床前研究 治疗(ERT)在保护受影响儿童的神经功能方面取得了成功。 不幸的是，这种治疗方法不能防止视网膜退化或由此导致的失明。 CLN2病。此外，ERT治疗需要长时间的脑室内临床基础。 每隔一周注射一次。利用狗的模型，将进行研究，以测试 假设联合一次性玻璃体内和脑脊液内注射AAV- TPP1基因治疗载体将防止视网膜退化和视觉中心的退化 中枢神经系统和保护功能视力，为在儿童中测试这种治疗方法奠定了基础 患有CLN2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.