Nonhuman Primate Model of Inherited Photoreceptor Degeneration

遗传性感光器变性的非人类灵长类动物模型

基本信息

批准号：
10717645
负责人：
MARTHA NEURINGER
金额：
$ 80.05万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10717645
关键词：
2 year old 4 year old Acceleration Adult Age Months Ally Animal Model Animals Area Artificial Insemination Assisted Reproductive Technology Bardet-Biedl Syndrome Birth Blindness Brain Bulla Characteristics Clinical Collaborations Cone DNA Sequence Alteration Development Disease Disease model Dose Electroretinography Embryo Exons Eye Family Gene Delivery Generations Genes Genetic Genetic Diseases Genotype Goals Hereditary Disease Histopathology Human Image Immunohistochemistry Infant Inherited Injections Kidney Kidney Diseases Knowledge Macaca Macaca mulatta Methods Modeling Monkeys Mutation Nature Obesity Operative Surgical Procedures Oregon Pathogenicity Pathology Patients Phenotype Photoreceptors Preclinical Testing Primates Reproduction Reproductive Biology Research Resources Retina Retinal Degeneration Retinal Diseases Retinal gene therapy Retinitis Pigmentosa Rodent Safety Serotyping Site Structure Study models Syndrome Testing Therapeutic Time Translations Usher Syndrome Vision Visual Visual evoked cortical potential animal breeding attenuation behavior measurement causal variant ciliopathy clinical practice cone-rod degeneration deaf disease-causing mutation early onset effective therapy efficacy testing experience fovea centralis gene augmentation therapy gene therapy genetic pedigree inherited retinal degeneration macula multimodality nonhuman primate novel novel therapeutics photoreceptor degeneration pre-clinical preservation prevent promoter retinal imaging screening sight restoration translational model translational potential vector vision development young adult

项目摘要

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.

项目概要失明可能是由许多导致视网膜退化的基因突变引起的，但其中大多数疾病没有治疗方法。安全有效治疗方法的开发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对其进行测试。因为非人类灵长类动物是唯一具有像人类一样的视网膜结构的动物，包括位于中央视网膜下方的黄斑视力，他们有潜力提供最准确和信息丰富的致盲疾病模型。事实上，缺乏此类模型已被认为是快速转化有前途的技术的主要障碍。临床用于预防和治疗失明的疗法。我们花了很多年的时间在俄勒冈国家灵长类研究中心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并伴有肾脏疾病的遗传性疾病这种疾病与人类的这种疾病非常相似。我们确定原因是基因突变 BBS7基因，对包括至少50个携带者的家系进行基因分型，并检查视网膜的性质组织病理学退化。我们现在建议传播这个模型，并用它来测试一个新基因治疗这种疾病和类似疾病的人类患者具有保留和恢复视力的巨大潜力。该提案的具体目标是： 1. 饲养Bardet-Biedl综合征动物并确定其发病特征和病程疾病。 2. 对患有这种疾病的动物进行基因治疗，并评估其保护或恢复中枢神经系统的能力想象。这种自发发生的猴子疾病与人类的 Bardet-Biedl 综合征非常相似患者。除了提供这种特定遗传疾病的模型外，它还提供了大型遗传疾病的模型。称为色素性视网膜炎的类似视网膜变性家族，它们共同构成了视网膜色素变性的主要遗传原因失明。这一发现为我们提供了传播和表征灵长类动物模型的独特机会遗传性视网膜变性的研究，并使用这些动物来测试基因治疗方法这整个类别的致盲疾病。我们的目标是开发一种保护和恢复人类视力的方法患有这种疾病和许多其他致盲疾病的患者。