Novel model systems for the study of cone disorders and other heritable retinal diseases

用于研究视锥细胞疾病和其他遗传性视网膜疾病的新型模型系统

• 批准号: 10439118
• 负责人: JEFFREY A. ROGERS
• 金额: $ 15万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439118
• 关键词: Affect; Animal Model; Animals; Biological Models; Blindness; California; Cell Therapy; Cells; Characteristics; Communities; Cone; Cone dystrophy; DNA sequencing; Development; Disease; Electroretinography; FDA approved; Fluorescein Angiography; Fundus photography; Genes; Genetic; Goals; Heritability; Human; Inherited; Innovative Therapy; Leber' s amaurosis; Macaca; Macaca mulatta; Modeling; Morbidity - disease rate; Mutation; Optical Coherence Tomography; Patients; Phenotype; Primates; RPE65 protein; Research; Retina; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; Rod; Series; Speed; Thinness; Translations; Vision research; Visual impairment; Work; base; behavior observation; disorder of macula of retina; effective therapy; efficacy testing; gene function; gene replacement therapy; gene therapy; genetic testing; human disease; human model; macula; nonhuman primate; novel; novel therapeutics; population survey; protein function; response

Project Summary/Abstract Retinal degeneration diseases are a common cause of untreatable blindness worldwide, affecting the lives of millions. The only FDA-approved treatment for these disorders is gene therapy for specific RPE65 mutations that cause Leber’s congenital amaurosis and retinitis pigmentosa. One major limitation to the development of effective therapies is the use of animal models that poorly replicate the human condition. Particularly for cone disorders, studies that use animals with a rod-dominant retina and no true macula have substantive limitations. By contrast, the cone-rich macula of nonhuman primates (NHP) closely mirrors that of the human retina. Consequently, well-defined NHP models of heritable retinal diseases, particularly cone disorders, that are more predictive of human conditions are necessary to more efficiently advance new therapies. We propose to develop a series of novel and spontaneous NHP models of human inherited retinal diseases. Behavioral observations of rhesus macaques (Macaca mulatta) at the California National Primate Research Center identified a series of macaques that displayed apparent visual impairment. Genetic testing showed that four animals are homozygous for a damaging mutation in the PDE6C gene, which has previously been associated with cone dystrophy in humans. Scotopic and photopic full-field electroretinograms performed on macaques homozygous for the PDE6C mutation demonstrated a relatively normal rod response but no cone response whatsoever. A subtle but characteristic bullseye maculopathy was identified using fundus photography, blue autofluorescence, and fluorescein angiography with concurrent foveal thinning using spectral-domain optical coherence tomography. Our genetic survey of this population also identified macaques with mutations in 7 other human retinal disease genes that are predicted to severely damage gene or protein function, pointing to possible additional new models. To develop the PDE6C primate model of cone dystrophy, and make this and other new NHP models available to the vision research community, we propose four Specific Aims: 1) to identify and genetically characterize new NHP models of human retinal disease via DNA sequencing, 2) to perform complete ophthalmic phenotyping of NHP models of retinal disease, 3) to breed a colony of NHPs with PDE6C cone dystrophy and 4) to compare cell-based and gene replacement therapies in macaques with PDE6C cone dystrophy mutations. Successful completion of this work will produce a well-characterized new animal model of inherited cone dystrophy with significantly greater similarity to human disease than existing models, thus providing substantially better translation to subsequent human trials. In addition, affected animals will be made available to the wider vision research community, and other new models with similar potential will be identified.

项目摘要/摘要 视网膜变性疾病是全世界无法治疗失明的常见原因，影响了 数百万的生活。这些疾病的唯一FDA批准治疗方法是特定的基因治疗 RPE65引起Leber的先天性效费和色素性视网膜炎的突变。一个主要 有效疗法发展的限制是使用不良复制的动物模型 人类状况。特别是对于锥体疾病，使用具有杆含量视网膜的动物的研究 而且没有真正的黄斑有实质性的局限性。相比之下，非人类的圆锥体大黄斑 私人（NHP）关闭了人类视网膜。因此，定义明确的NHP模型 可遗传的残留疾病，尤其是锥体疾病，更可预测人类状况 更有效地推进新疗法所必需的。我们建议开发一系列小说， 人类继承的残余疾病的赞助NHP模型。恒河主的行为观察 加利福尼亚国家灵长类动物研究中心的猕猴（Macaca Mulatta）确定了一系列 猕猴显示出明显的视觉障碍。基因测试表明四只动物是 PDE6C基因中有害突变的纯合子，以前与之相关 人类的锥体营养不良。在猕猴上执行的SCOTOPIC和PHOTOPIC全场电视图 PDE6C突变的纯合子表现出相对正常的杆响应，但没有锥体 反应。使用眼底鉴定出一种微妙但特征性的牛s刺伤 摄影，蓝色自动荧光和荧光素血管造影，并发叶片稀疏 光谱域光学相干断层扫描。我们对该人群的遗传调查也确定了 在其他7种人类残留疾病基因中具有突变的猕猴，预计将严重损害 基因或蛋白质功能，指出可能的其他新模型。开发PDE6C灵长类动物 锥体营养不良的模型，并使视觉研究可用 社区，我们提出了四个具体目标：1）识别并普遍表征新的NHP模型 通过DNA测序的人类残留疾病，2）进行NHP的完整眼科表型 视网膜疾病模型，3）繁殖NHP的菌落具有PDE6C锥体营养不良和4） PDE6C锥体营养不良突变的猕猴中基于细胞的和基因替代疗法。 这项工作的成功完成将产生一种特征良好的新动物模型的继承模型 锥体营养不良与人类疾病的相似性明显高于现有模型，因此 为随后的人类试验提供了更好的翻译。另外，受影响的动物将 可供更广泛的视觉研究社区以及其他具有相似潜力的新模型 将被确定。