权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10483221
负责人：
RUI CHEN
金额：
$ 129.42万
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 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10483221
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.

项目总结/文摘