Diversity Supplement: Advancing novel therapies for optic neuropathy with a nonhuman primate model

多样性补充：利用非人类灵长类动物模型推进视神经病变的新疗法

基本信息

批准号：
10844261
负责人：
Sara Michelle Thomasy
金额：
$ 5.54万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
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：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10844261
关键词：
Acceleration Affect Age Anatomy Animal Model Animals Apoptosis Autosomal Dominant Optic Atrophy Axon Behavioral Blindness Breeding Cell Density Cell Nucleus Cell physiology Cellular Structures Characteristics Clinical Color Visions Communities Contralateral Data Dendrites Development Disease Disease Progression Disease model Drug Kinetics Dynamin Electroretinography Euthanasia Exhibits Eye Flavoproteins Fluorescence Functional disorder Future Gene Mutation Genes Genetic Glaucoma Goals Heritability Heterozygote Histologic Homozygote Human Immunohistochemistry Individual Inflammation Inherited Innovative Therapy Macaca Macaca mulatta Measures Missense Mutation Mitochondria Modeling Monitor Morbidity - disease rate Morphology Multimodal Imaging Mutation Nerve Nerve Degeneration Neurodegenerative Disorders Optic Disk Optic Nerve Optic atrophy 1 Oxidative Stress Pallor Pathologic Pathology Pathway interactions Patients Peripheral Persons Phenotype Physiology Production Protein Isoforms Proteins Research Resolution Resources Retina Retinal Cone Retinal Ganglion Cells Scotoma Signal Transduction Speed Testing Thick Thinness Time Trauma Vision Visual Visual Acuity Visual impairment achromatopsia autosome cell injury cohort density differential expression dyschromatopsia effective therapy human tissue improved mRNA Expression macula mouse model multiple omics neuronal cell body new therapeutic target nonhuman primate novel novel therapeutic intervention novel therapeutics optic nerve disorder optical imaging programs protein expression retinal imaging retinal nerve fiber layer sight restoration therapeutic evaluation therapy development transcriptome transcriptomics vision science

项目摘要

PROJECT SUMMARY Optic neuropathies are common causes of blindness worldwide, affect the lives of millions, and lack effective treatments to restore vision. Autosomal dominant optic atrophy (ADOA) is an inherited optic neuropathy that affects ~3 per 100,000 people worldwide, results in vision impairment, and has no treatment. It is primarily due to mutations in the optic atrophy 1 (OPA1) gene, which encodes a mitochondrial dynamin-related protein critical for mitochondrial stability and energy production. A major limitation to the development of effective therapies for optic neuropathies is the use of animal models that poorly replicate the human condition. Particularly for optic nerve and RGC disorders, studies would benefit from the use nonhuman primates (NHP) with optic nerve and retinal anatomy, physiology and pathology, which closely mirrors that of humans. Consequently, well-defined NHP models of optic neuropathy that are more predictive of human conditions are necessary to efficiently advance new therapies. We identified rhesus macaques heterozygous and homozygous for a missense mutation in OPA1 that demonstrate optic nerve head pallor and thinning of the retinal nerve fiber layer in comparison to wildtype controls; these findings are consistent with ADOA in human patients. We will fully define this NHP model of ADOA and determine its impact on RGC structure and function longitudinally over a 5-year period. Specifically, we will assess the onset and progression of retinal dysfunction utilizing electroretinography, retinal flavoprotein fluorescence and visual testing. Importantly, we will correlate the clinical findings with detailed transcriptomic, histologic, and immunohistochemical data for a comprehensive characterization of this NHP model of ADOA. The ADOA transcriptome from NHPs is highly likely to identify novel genes and pathways involved in RGC pathology and neurodegeneration as well as validate previously implicated pathways thus revealing new therapeutic targets. We will also perform detailed histological, immunohistochemical and ultrastructural analyses to assess RGC soma, axons and dendrites as well as their mitochondrial size and number in the macula, papillomacular bundle, and periphery of the retina. Finally, through selective breeding of ADOA-affected NHPs, we will generate a supply of macaques heterozygous and homozygous for the OPA1 mutation for future study. To make this new NHP optic neuropathy model available for therapeutic testing, we propose three Specific Aims: 1) To define the morphologic features and phenotypic spectrum of a NHP model of ADOA, 2) to determine the impact of the OPA1 A8S mutation on RGC function in NHPs, and 3) to determine mRNA and protein expression in RGCs of ADOA-affected NHPs. Once the most predictive endpoints of disease and sufficient animals with ADOA are identified, we will pursue additional studies of etiopathogenesis and novel therapeutic strategies. This comprehensive NHP model of ADOA will be a highly valuable resource for the vision science and neurodegenerative disease communities.

项目概要视神经病变是全世界失明的常见原因，影响数百万人的生活，并且缺乏有效的治疗方法恢复视力的治疗。常染色体显性视神经萎缩（ADOA）是一种遗传性视神经病变，全球每 100,000 人中约有 3 人受到影响，导致视力障碍，且无法治疗。这主要是由于视神经萎缩 1 (OPA1) 基因突变，该基因编码线粒体动力相关关键蛋白用于线粒体稳定性和能量产生。开发有效疗法的主要限制视神经病变是使用不能很好地复制人类状况的动物模型。特别适用于光学神经和 RGC 疾病，研究将受益于使用具有视神经和视神经的非人类灵长类动物（NHP）视网膜解剖学、生理学和病理学，与人类的视网膜解剖学、生理学和病理学非常相似。因此，明确定义的更能预测人类状况的 NHP 视神经病变模型对于有效地推进新疗法。我们鉴定了恒河猴杂合子和纯合子的错义突变与 OPA1 相比，显示视神经乳头苍白和视网膜神经纤维层变薄野生型对照；这些发现与人类患者的 ADOA 一致。我们将完整定义这个NHP模型 ADOA 并确定其在 5 年期间对 RGC 结构和功能的纵向影响。具体来说，我们将利用视网膜电图、视网膜黄素蛋白来评估视网膜功能障碍的发生和进展荧光和视觉测试。重要的是，我们将把临床发现与详细的转录组学相关联，组织学和免疫组织化学数据，用于全面表征 ADOA 的 NHP 模型。 NHP 的 ADOA 转录组极有可能识别出与 RGC 相关的新基因和途径病理学和神经退行性变以及验证先前涉及的途径，从而揭示新的治疗目标。我们还将进行详细的组织学、免疫组织化学和超微结构分析评估 RGC 胞体、轴突和树突及其在黄斑中的线粒体大小和数量，乳头黄斑束和视网膜周边。最后，通过受 ADOA 影响的 NHP 的选择性育种，我们将生成 OPA1 突变的杂合子和纯合子猕猴供将来研究。为了使这种新的 NHP 视神经病变模型可用于治疗测试，我们提出了三个具体目标： 1) 定义 ADOA NHP 模型的形态特征和表型谱，2) 确定 OPA1 A8S 突变对 NHP 中 RGC 功能的影响，以及 3) 确定 mRNA 和蛋白质表达受 ADOA 影响的 NHP 的 RGC 中。一旦获得了最具预测性的疾病终点并且有足够的动物 ADOA 已确定，我们将继续研究发病机制和新的治疗策略。这 ADOA 的综合 NHP 模型将成为视觉科学和视觉科学领域的宝贵资源。神经退行性疾病社区。