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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

基本信息

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
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/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

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.

项目总结