Nonhuman Primate Model of Inherited Photoreceptor Degeneration

项目摘要 失明可能是由许多基因突变导致视网膜变性，但大多数这些 疾病没有治疗方法。安全有效的治疗方法的发展关键取决于 在人类患者中使用它们之前，能够在适当的动物模型中对其进行测试。因为非人类 灵长类动物是唯一具有与人类相似的视网膜结构的动物，包括位于中央视网膜下的黄斑。 由于这些模型对视力的影响，它们有可能提供最准确和信息量最大的致盲疾病模型。 事实上，缺乏这种模式已被确定为快速翻译有前途的 用于预防和治疗失明的临床用途。 我们在俄勒冈州国家灵长类动物研究中心花了很多年的时间来筛选大型猕猴群 自然发生的视网膜疾病中心。我们最近发现了一个恒河猴家族， Bardet-Biedl综合征，一种导致严重视网膜变性的遗传性疾病， 疾病，这非常类似于这种疾病的人类形式。我们确定原因是 BBS 7基因，对包括至少50名携带者的家系进行基因分型，并检查视网膜病变的性质。 通过组织病理学观察到的变性。我们现在建议推广这个模型，并使用它来测试一个新的基因 在这种疾病和类似疾病的人类患者中，这种治疗具有高度的潜力来保持和恢复视力。 这项建议的具体目标是： 1.为了繁殖Bardet-Biedl综合征动物，并确定其特征和时间进程， 疾病 2.为了给患有这种疾病的动物提供基因治疗，并评估其保护或恢复中枢神经系统的能力， 视野 这种自发发生的猴子疾病与在人类中观察到的Bardet-Biedl综合征非常相似 患者除了提供这种特定遗传疾病的模型外， 一个类似的视网膜变性家族，称为色素性视网膜炎，它们共同是视网膜变性的主要遗传原因。 失明这一发现为我们提供了一个独特的机会来传播和描述灵长类动物模型 并使用这些动物来测试基因治疗方法来治疗遗传性视网膜变性， 这一类致盲性疾病我们的目标是开发一种方法来保护和恢复人类的视力 患有这种疾病和许多其他致盲疾病的患者。

PROJECT SUMMARY Blindness can be caused by many genetic mutations that lead to degeneration of the retina, but most of these diseases have no treatments. The development of safe and effective treatments critically depends on the ability to test them in appropriate animal models before using them in human patients. Because nonhuman primates are the only animals with retinal structure like humans, including the macula that underlies central vision, they have the potential to provide the most accurate and informative models of blinding diseases. Indeed, the lack of such models has been identified as a major impediment to the rapid translation of promising therapies to clinical use for preventing and treating blindness. We have spent many years screening the large macaque colony at the Oregon National Primate Research Center for naturally-occurring retinal diseases. We recently discovered a family of rhesus monkeys with Bardet-Biedl syndrome, an inherited disease resulting in severe retinal degeneration combined with kidney disease, which closely resembles the human form of this disorder. We identified the cause as a mutation in the BBS7 gene, genotyped a pedigree including at least 50 carriers, and examined the nature of the retinal degeneration by histopathology. We now propose to propagate this model, and use it to test a novel gene therapy with high potential to preserve and restore sight in this and similar diseases in human patients. The specific aims of this proposal are: 1. To breed animals with Bardet-Biedl syndrome and determine the characteristics and time course of the disease. 2. To deliver a gene therapy to animals with this disease and evaluate its ability to preserve or restore central vision. This spontaneously-occurring monkey disorder closely mirrors Bardet-Biedl syndrome as seen in human patients. In addition to providing a model of this specific genetic disease, it also provides a model for the large family of similar retinal degenerations called retinitis pigmentosa that together are a major inherited cause of blindness. This discovery provides us with a unique opportunity to propagate and characterize a primate model of an inherited retinal degeneration and to use these animals to test gene therapy approaches to therapy for this entire class of blinding disorders. Our goal is to develop a method to preserve and restore vision in human patients with this and many other blinding diseases.