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: 10613482
• 负责人: MARTIN L KATZ
• 金额: $ 38.26万
• 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/10613482
• 关键词: Affect; Age Months; Binding Proteins; Blindness; Blood; Brain; CLN2 gene; CNS degeneration; Canis familiaris; Cell Fraction; Cell membrane; Cell surface; Cells; Central Nervous System; 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; IGF Type 2 Receptor; Infusion procedures; Injections; Life; Longevity; Lysosomal Storage Diseases; Lysosomes; Mediating; Meditation; Methods; Modeling; Mutation; Nervous System Physiology; Neurologic; Neurologic Signs; Neuronal Ceroid-Lipofuscinosis; Organ; Pathology; Pathway interactions; Patients; Periodicals; Protein Secretion; 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; 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

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.

项目概要 拟议研究的主要目的是评估 AAV 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）的介导基因治疗 CLN2 神经元蜡样脂褐素沉积症 (NCL) 犬模型中的变性，特别是当它们 与功能性视力有关。 CLN2 疾病是由可溶性溶酶体酶缺乏引起的 三肽基肽酶-1 (TPP1) 由 TPP1 突变引起。具有无效突变的腊肠犬 TPP1 用于支持 CNS 酶替代品开发的临床前研究 疗法（ERT）已成功地保留受影响儿童的神经功能。 不幸的是，这种治疗并不能预防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治疗 终身每隔一周注射一次。将使用狗模型进行研究以测试 假设联合一次性玻璃体腔内和脑脊液内注射 AAV- TPP1基因治疗载体将预防视网膜变性和视觉中枢变性 中枢神经系统并保留功能性视力，为在儿童中测试这种治疗方法奠定了基础 患有 CLN2 疾病。