ANIMAL MODEL FOR GENE THERAPY OF INHERITED DISORDERS

这笔赠款的目标是维持和繁殖一群携带球状细胞白质营养不良症(GLD)的恒河猴，并描述GLD在纯合子患者中发生的特征。该项目的长期目标是开发一种非人类灵长类动物模型，用于先天性新陈代谢疾病的基因治疗。这群恒河猴是世界上唯一一群非人类灵长类动物，在其中遗传性溶酶体疾病已被识别、繁殖并可用于研究。没有其他非人类灵长类动物模型可以用来测试患有遗传病的动物各种治疗干预的实际临床效果。该殖民地有21只携带者猴子。它们将被自然或人工地在社交场所饲养和繁殖。胎儿的发育将通过超声波进行监测。在出生前或出生后，通过生化和聚合酶链式反应将婴儿诊断为纯合子正常、杂合携带者或纯合子感染。婴儿将在临床、行为、神经生理学、病理学和神经成像方面进行特征描述。这些数据将在未来的应用中用作比较治疗干预效果，特别是基因治疗效果的基线。我们认为，这项提案的具体目标跨越了几个NIH研究所的利益。其中包括NCRR(动物模型，生物技术)、NINDS(婴幼儿神经遗传障碍)、NIDDKD(开发先天性代谢性疾病的躯体基因治疗方法)和NICHHD(妊娠期治疗，发育异常)。在患有遗传病的非人类灵长类动物模型中研究基因治疗方案的体内有效性和安全性的能力，将是推进人类遗传药物前景的有力工具。

The objectives of this grant are to maintain and propagate a colony of rhesus monkeys that are carriers of globoid cell leukodystrophy (GLD) and to characterize GLD as it occurs in homozygous affected individuals. The long-term goal of this project is to develop a nonhuman primate animal model for gene therapy of inborn errors of metabolism. This colony of rhesus monkeys is the only colony of nonhuman primates in the world in which an inherited lysosomal disorder has been recognized, propagated, and is available for study. No other nonhuman primate model is available in which to test the actual clinical effectiveness of various therapeutic interventions in animals with a genetic disease. There are 21 carrier monkeys in the colony. They will be socially housed and bred naturally or artificially. Fetal growth will be monitored by ultrasound. Before or after birth, infants will be diagnosed by biochemistry and polymerase chain reaction as homozygous normal, heterozygous carrier, or homozygous affected. Infants will be characterized clinically, behaviorally, neurophysiologically, pathologically, and by neuroimaging. These data will be used in future applications as a baseline against which to compare the effects of therapeutic interventions, particularly gene therapy. We believe the specific aims of this proposal span the interests of several NIH institutes. These include the NCRR (animal models, biotechnology), the NINDS (neurogenetic disorders of infancy and childhood), the NIDDKD (development of somatic gene therapy approaches for inborn metabolic diseases), and the NICHHD (therapeutics during pregnancy, developmental abnormalities). The ability to study the in vivo efficacy and safety of gene therapy protocols in a nonhuman primate animal model with a genetic disease will be a powerful tool for advancing the prospects of genetic medicine in humans.