Gene therapy for preserving the visual system in lysosomal storage diseases

在溶酶体贮积病中保护视觉系统的基因疗法

• 批准号: 10815994
• 负责人: MARTIN L KATZ
• 金额: $ 6.2万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10815994
• 关键词: Affect; Blindness; CLN2 gene; CNS degeneration; Central Nervous System; Cerebrospinal Fluid; Child; Clinic; Development; Disease; Enzymes; Gene Transduction Agent; Injections; Life; Lysosomal Storage Diseases; Mediating; Mutation; Nervous System Physiology; Neuronal Ceroid-Lipofuscinosis; Research; Retina; Retinal Degeneration; Retinal gene therapy; Safety; Testing; Tissues; Vision; Visual; Visual Pathways; Visual System; canine model; enzyme replacement therapy; gene therapy; null mutation; preclinical study; preservation; prevent; tripeptidyl aminopeptidase

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-based 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.

项目摘要 拟议研究的主要目的是评估AAV的安全性和功效 介导的基因治疗，以防止进行性视网膜和中枢神经系统（CNS） CLN2神经元粘膜脂肪促脂肪促脂肪促脂肪促（NCL）的犬模型中的变性，尤其是当它们 与功能视觉有关。 CLN2疾病是由于可溶性溶酶体酶缺乏而引起的 由TPP1突变引起的三肽基肽酶-1（TPP1）。带有无效突变的腊肠犬 TPP1用于支持CNS酶替代的发展的临床前研究 在保留受影响儿童的神经功能方面已成功的治疗（ERT）。 不幸的是，这种治疗方法不能阻止视网膜变性或导致的失明 CLN2病。此外，ERT治疗需要较长的基于诊所的脑室内脑室 每隔一周注射一次。使用狗模型，将进行研究以测试 假设授予的一次性玻璃体内和脑脊液内给药的假设 TPP1基因疗法向量将防止视觉中心的视网膜变性和变性 中枢神经系统并保留功能视觉，为在儿童中测试这种治疗奠定了基础 患有CLN2疾病。