Advancing novel therapies for optic neuropathy with a nonhuman primate model

利用非人灵长类动物模型推进视神经病变的新疗法

• 批准号: 10594226
• 负责人: Sara Michelle Thomasy
• 金额: $ 69.33万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 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/10594226
• 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

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.

项目摘要 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。 治疗恢复视力。常染色体显性视神经萎缩（ADOA）是一种遗传性视神经病变， 影响全球每100，000人中约3人，导致视力受损，并且无法治疗。主要是由于 视神经萎缩1（OPA 1）基因突变，该基因编码一种线粒体动力蛋白相关蛋白， 维持线粒体稳定和能量产生发展有效治疗的一个主要限制因素是 视神经病变是使用动物模型，而动物模型很难复制人类的状况。特别是对于光学 神经和RGC疾病，研究将受益于使用非人灵长类动物（NHP）的视神经和 视网膜解剖学，生理学和病理学，这密切反映了人类。因此，定义明确 更能预测人类状况的视神经病变的NHP模型是有效地 推进新疗法。我们鉴定了一种错义突变的杂合子和纯合子恒河猴 在OPA 1中，与 野生型对照;这些发现与人类患者中的ADOA一致。我们将全面定义这个NHP模型 的影响，并确定其对研资局结构和职能的纵向影响，在五年期间。具体地说， 我们将利用视网膜电图、视网膜黄素蛋白 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， 组织学和免疫组织化学数据，用于ADOA NHP模型的综合表征。 来自NHP的ADOA转录组极有可能鉴定出参与RGC的新基因和途径 病理学和神经变性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 为了评估黄斑中的RGC索马、轴突和树突以及它们的线粒体大小和数量， 乳头状斑束和视网膜周边。最后，通过对受ADOA影响的NHP进行选择性育种， 我们将为将来的研究提供OPA 1突变的杂合和纯合猕猴。 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)为了确定ADOA的NHP模型的形态学特征和表型谱，2）确定ADOA的NHP模型的表型谱， OPA 1 A8 S突变对NHP中RGC功能的影响，以及3）确定mRNA和蛋白质表达 在受ADOA影响的NHP的RGC中。曾经是疾病最具预测性的终点， ADOA的确定，我们将追求额外的研究，发病机制和新的治疗策略。这 ADOA的综合NHP模型将是视觉科学的一个非常有价值的资源， 神经退行性疾病社区。