Nonhuman Primate Model of Inherited Photoreceptor Degeneration

项目总结 失明可能是由许多导致视网膜退化的基因突变引起的，但大多数 疾病是没有治疗方法的。安全有效的治疗方法的发展关键取决于 在将它们用于人类患者之前，能够在适当的动物模型中测试它们。因为非人类 灵长类动物是唯一像人类一样具有视网膜结构的动物，包括位于中央的黄斑。 在视觉方面，它们有可能提供最准确和最有信息量的致盲疾病模型。 事实上，缺乏这样的模式已被认为是快速翻译Promising的一个主要障碍 防盲治盲的临床应用。 我们花了很多年在俄勒冈州国家灵长类动物研究中心对大型猕猴群体进行筛选 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综合征是一种遗传性疾病，可导致严重的视网膜变性并肾脏 疾病，这种疾病与人类的这种疾病形式非常相似。我们确定的原因是基因突变 BBS7基因，对包括至少50名携带者的家系进行了基因分型，并检查了视网膜的性质 通过组织病理学的退化。我们现在建议推广这个模型，并用它来测试一种新的基因 对于这种疾病和人类患者的类似疾病，具有保存和恢复视力的高潜力治疗。 这项建议的具体目标是： 1.选育Bardet-Biedl综合征动物并测定其发病特点和时间进程 疾病。 2.为患有这种疾病的动物提供基因治疗，并评估其保存或恢复中枢的能力 幻象。 这种自发发生的猴子疾病与人类的Bardet-Biedl综合征非常相似 病人。除了提供这种特定遗传病的模型外，它还为大型 类似的视网膜变性家族，称为视网膜色素变性，共同是遗传性视网膜变性的主要原因 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模型 遗传性视网膜变性的研究，并利用这些动物来测试基因治疗方法 这一整类的失明障碍。我们的目标是开发一种保存和恢复人类视力的方法 患有这种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.