Sustained delivery of therapeutics to the visual system using genetically modified autologous mesenchymal stem cells to treat blinding diseases

项目总结 这项研究的目的是评估一种新方法的安全性和有效性。 将治疗药物输送到中枢神经系统(CNS)和视网膜来治疗疾病 与视力障碍有关。经过检验的假设是自体基因 经修饰的间充质干细胞(MSCs)可作为一种有效的持续给药载体 用于治疗失明的大脑视觉中心和视网膜的治疗药物 由视觉系统的一个或多个部分的病理引起的疾病。概念证明 研究将使用经过充分表征和验证的CLN2犬模型进行 神经元性蜡样脂褐素沉积症，是一种以广泛传播为特征的儿科疾病 由于双侧视网膜的退化而导致的进行性视力丧失的神经变性 视觉处理中心在大脑，认知和运动能力下降，以及癫痫发作。CLN 2 这种疾病是由TPP1基因突变引起的，这种突变导致可溶性溶酶体缺乏。 三肽基肽酶-1(TPP1)。假设将TPP1提供给CNS使用 植入经基因改造可产生和分泌的自体MSCs 该蛋白质将改善犬模型中与疾病相关的视力损失。

PROJECT SUMMARY The objective of the proposed research is to evaluate the safety and efficacy of a novel method of delivering therapeutics to the central nervous system (CNS) and the retina to treat diseases associated with visual impairment. The hypothesis tested is that autologous genetically modified mesenchymal stem cells (MSCs) can serve as effective vehicles for sustained delivery of therapeutics to visual centers in the brain and to the retina for the treatment of blinding diseases that result from pathology in one or more parts of the visual system. Proof of concept studies will be performed using a well-characterized and validated canine model of CLN2 neuronal ceroid lipofuscinosis, a disease with pediatric onset characterized by widespread neurodegeneration resulting in progressive loss of vision due to degeneration of both the retina and visual processing centers in the brain, cognitive and motor decline, and seizures. CLN2 disease is caused by mutations in TPP1, which result in deficiencies of the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). It is hypothesized that providing TPP1 to the CNS using implantation of autologous MSCs that have been genetically modified to produce and secrete the protein will ameliorate disease-related vision loss in the canine model.