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.

项目摘要视神经病是全球失明的常见原因，影响了数百万的生活，并且缺乏有效恢复视力的治疗方法。常染色体显性视神经萎缩（ADOA）是一种遗传性的神经病，全球每10万人影响约3人，导致视力障碍，没有治疗。主要是由于到视神经萎缩1（OPA1）基因中的突变，该基因编码线粒体动力蛋白相关蛋白关键用于线粒体稳定性和能量产生。开发有效疗法的主要限制光学神经病是使用不良复制人类状况的动物模型的使用。特别是用于光学元件神经和RGC疾病，研究将受益于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，生理和病理学，它们与人类的相似。因此，定义明确更有效地预测人类条件的视神经病变的NHP模型是有效的推进新疗法。我们确定了猕猴的杂合子和纯合的错义突变在OPA1中，与视网膜神经纤维层相比野生型对照；这些发现与人类患者的ADOA一致。我们将充分定义此NHP模型 ADOA并在5年内纵向确定其对RGC结构和功能的影响。具体来说，我们将评估使用视网膜造影，视网膜黄蛋素的视网膜功能障碍的发作和进展荧光和视觉测试。重要的是，我们将将临床发现与详细的转录组相关联组织学和免疫组织化学数据，用于对ADOA的NHP模型进行全面表征。来自NHP的ADOA转录组很有可能鉴定RGC中涉及的新基因和途径病理学和神经退行性以及验证先前涉及的途径，从而揭示了新的治疗靶标。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RGC的soma，轴突和树突以及黄斑中的线粒体大小和数字，视网膜的乳头状束和周围。最后，通过选择性育种受ADOA影响的NHP，我们将为OPA1突变提供猕猴的杂合和纯合子，以进行未来研究。为了使这种新的NHP神经病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光谱，2）确定 OPA1 A8S突变对NHP中RGC功能的影响，以及3）确定mRNA和蛋白质表达在受ADOA影响的NHP的RGC中。曾经是疾病和足够动物的最预测性终点确定了ADOA，我们将进行其他有关疗法生成和新型治疗策略的研究。这 ADOA的全面NHP模型将成为视觉科学和神经退行性疾病群落。