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

基本信息

批准号：
10393698
负责人：
MARTIN L KATZ
金额：
$ 37.02万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
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/10393698
关键词：
Affect Age-Months Binding Proteins Blindness Blood Brain CLN2 gene CNS degeneration Canis familiaris Cell Fraction Cell membrane Cell surface Cells Cerebrospinal Fluid Child Clinic Clinical County DNA Development Disease Disease model Distant Dog Diseases Endocytosis Endoplasmic Reticulum Endosomes Enzymes Extracellular Space Eye Gene Transduction Agent Genes Goals Golgi Apparatus Human Infusion procedures Injections Life Longevity Lysosomal Storage Diseases Lysosomes Mediating Methods Modeling Mutation Nervous System Physiology Neuraxis Neurologic Neurologic Signs Neuronal Ceroid-Lipofuscinosis Organ Pathology Pathway interactions Patients Periodicity Proteins Recombinant Proteins Recombinants Research Retina Retinal Degeneration Retinal gene therapy Safety Site Structure System Testing Time Tissues Variant Vision Visual Visual Pathways Visual system structure Vitreous humor adduct base canine model cellular transduction early childhood efficacy testing end stage disease enzyme replacement therapy follow-up gene therapy in vivo intravitreal injection lysosomal proteins mannose 6 phosphate null mutation preclinical study preservation prevent receptor targeted delivery tripeptidyl aminopeptidase uptake

项目摘要

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.

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治疗需要长诊断室内室内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。