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

基本信息

批准号：
10247503
负责人：
RUI CHEN
金额：
$ 140.63万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
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/10247503
关键词：
Affect Animal Model Animals Architecture Biological Models Blindness Breeding California Catalytic Domain Cell Therapy Cells Characteristics Clinical Trials Code Communities Cone Cone dystrophy Contralateral DNA DNA sequencing Development Disease Disease Progression Disease model Electroretinography Ensure Eye FDA approved Fluorescein Angiography Fundus photography Genes Genetic Genomics Goals Health Heritability Human Imaging Techniques Inbreeding Individual Inherited Injections Innovative Therapy Laboratories Leber&apos s amaurosis Macaca Macaca mulatta Missense Mutation Modeling Monitor Morbidity - disease rate Mutation Optical Coherence Tomography Pathologic Patients Phenotype Photoreceptors Primates Proteins RPE65 protein Research Retina Retinal Cone Retinal Degeneration Retinal Diseases Retinal macula Retinitis Pigmentosa Rod Rodent Sampling Series Speed Surveys Testing Therapeutic Thinness Time Translations Variant Vision Vision research Visual impairment Work achromatopsia animal colony arm base disorder of macula of retina effective therapy efficacious treatment efficacy testing gene function gene replacement gene replacement therapy gene therapy genetic testing human disease human model improved macula mutation carrier nonhuman primate novel ocular imaging programs protein function response retinal progenitor cell screening success

项目摘要

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 model systems that poorly replicate the human condition. Particularly for cone disorders, studies that use model systems with a rod-dominant retina and no true macula have substantive limitations. We propose to develop a series of novel and spontaneous animal models of human inherited retinal diseases. In preliminary analyses, we have identified a new spontaneous model directly relevant to human retinal disease. Genetic testing identified four individuals homozygous for a naturally occurring damaging mutation in the PDE6C gene, which has previously been associated with cone dystrophy in humans. Scotopic and photopic full-field electroretinograms performed on animals homozygous for the PDE6C mutation demonstrated a relatively normal rod response but no cone response whatsoever. A subtle but characteristic retinopathy was identified using fundus photography, blue autofluorescence, and fluorescein angiography with concurrent foveal thinning using spectral-domain optical coherence tomography. Our genetic survey also identified individuals 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 new model of PDE6C cone dystrophy, and make this and other new models available to the vision research community, we propose four Specific Aims: 1) to identify and genetically characterize new animal models of human retinal disease via DNA sequencing, 2) to perform complete ophthalmic phenotyping of the new models of retinal disease, 3) to breed a colony of animals with PDE6C cone dystrophy and 4) to compare cell-based and gene replacement therapies in these subjects 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的失明的常见原因，影响了数百万的生活。这些疾病的唯一批准的治疗方法是针对引起Leber先天性效费和色素性视网膜炎的特定RPE65突变的基因治疗。开发有效疗法的一个主要局限性是使用不良复制人类状况的模型系统。特别是对于锥体疾病，将模型系统与杆位视网膜和没有真正的黄斑没有的研究具有实质性局限性。我们建议开发一系列新型和赞助的人类遗传残留疾病的动物模型。在初步分析中，我们确定了一种与人类残留疾病直接相关的新赞助模型。基因测试确定了四个个体，纯合为PDE6C基因中天然发生的损伤突变，该基因以前与人类的锥形营养不良有关。对PDE6C突变纯合的动物进行的Scotic和Photopic全场电视图显示出相对正常的杆反应，但没有任何锥体反应。使用眼底摄影，蓝色自动荧光和荧光素血管造影，使用光谱域光学相干性层析成像鉴定出微妙但特征性的视网膜病变。我们的遗传调查还确定了在其他7种人类视网膜疾病基因中具有突变的个体，这些基因被预测会严重损害基因或蛋白质功能，并指出可能的其他新模型。 To develop the new model of PDE6C cone dystrophy, and make this and other new models available to the vision research community, we propose four Specific Aims: 1) to identify and genetically characterize new animal models of human residual disease via DNA sequencing, 2) to perform complete ophthalmic phenotyping of the new models of residual disease, 3) to breed a colony of animals with PDE6C cone dystrophy and 4) to compare cell-based以及PDE6C锥体营养不良突变中这些受试者中的基因替代疗法。这项工作的成功完成将产生一个良好的遗传性锥体营养不良的新动物模型，其与人类疾病的相似性明显高于现有模型，从而为随后的人类试验提供了更大的翻译。此外，将为更广阔的视力研究社区提供受影响的动物，并确定其他具有相似潜力的新模型。