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Therapeutic Editing of Rod Glycolysis Rescues Retinal Degeneration

杆状糖酵解的治疗性编辑可挽救视网膜变性

基本信息

批准号：
10607717
负责人：
Nicholas David Nolan
金额：
$ 4.77万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2023-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607717
关键词：
Ablation Address Adult Aerobic Affect Age Anemia Atrophic Carbon Cells Cessation of life Choroid Citric Acid Cycle Clinical Treatment Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Cone Coupling Disease Disease Progression Enzymes Functional disorder Funding Gene Mutation Genes Genetic Genetic Recombination Glucose Glycolysis Goals Guide RNA Human Hypoxia Inducible Factor Individual Inherited Injections Investigational New Drug Application Kidney Knock-out Knowledge Lead Mediating Metabolic Metabolic Pathway Methods Modeling Mouse Strains Mus Mutation Neurodegenerative Disorders Oral Administration Outcome Patients Phase Photoreceptors Process Procollagen-Proline Dioxygenase Production Proteins RPE65 protein Retina Retinal Cone Retinal Degeneration Retinal Diseases Retinal Dystrophy Retinitis Pigmentosa Rod Role Safety Source Starvation Structure of retinal pigment epithelium Subgroup Teenagers Testing Therapeutic Tissue Sample Translating Ubiquitination VHL protein Vertebrate Photoreceptors aerobic glycolysis antagonist bHLH-PAS factor HLF bench-to-bedside translation blind clinically significant cost efficacy evaluation gene therapy hemangioblastoma inducible Cre mouse model normoxia novel novel strategies oxidation pharmacologic phosphoric diester hydrolase photoreceptor degeneration preservation promoter repaired response retinal rods therapeutic genome editing tool vector

项目摘要

PROJECT SUMMARY Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy, caused by more than 3100 mutations in 80 genes that are primarily specific to rod photoreceptors. Following the major rod death phase, cone death occurs regardless of the underlying gene mutations. However, there exists a knowledge gap in understanding how aerobic glycolysis in cones impacts the delicate “metabolic coupling” between cones and retinal pigment epithelium (RPE) in RP. In this proposal, we hypothesize that reprogramming rod and cone aerobic glycolysis can promote cone survival in RP independent of the underlying rod-specific gene mutations. To test this hypothesis, we propose the following specific aims. In Aim 1, we will determine whether enhanced aerobic glycolysis in cone photoreceptors can promote their survival in a novel genetic mouse model. In Aim 2, we will test the potential of gene therapy to slow photoreceptor degeneration by enhancing aerobic glycolysis in mouse models of RP and characterizing the metabolic changes that occur. Lastly, in Aim 3, we will evaluate the safety profile of the gene therapy described in Aim 2.

项目总结视网膜色素变性(RP)是最常见的遗传性视网膜营养不良，由3100多个突变引起在80个主要针对杆状感光器的基因中。在主要杆状死亡阶段之后，圆锥体死亡无论潜在的基因突变如何，都会发生。然而，在理解上存在着知识鸿沟视锥细胞中的有氧糖酵解如何影响视锥细胞和视网膜色素之间微妙的“代谢偶联” RP中的上皮(RPE)。在这个方案中，我们假设重新编程的杆状和锥状有氧糖酵解可以促进视锥细胞在RP中的存活，而不依赖于潜在的杆状特异基因突变。为了测试这一点假设，我们提出了以下具体目标。在目标1中，我们将确定增强有氧锥体光感受器的糖酵解可以促进它们在一种新的遗传小鼠模型中的存活。在目标2中，我们将通过促进小鼠有氧糖酵解来测试基因治疗延缓光感受器退化的可能性 RP的模型和所发生的代谢变化的特征。最后，在目标3中，我们将对其安全性进行评估目标2中描述的基因疗法简介。