Therapeutic Editing of Rod Glycolysis Rescues Retinal Degeneration

项目摘要 视网膜色素变性（RP）是最常见的遗传性视网膜营养不良，由超过3100个突变引起 在80个基因中主要是针对视杆细胞的。在主要的视杆细胞死亡阶段之后，视锥细胞死亡 无论潜在的基因突变如何。然而，在理解方面存在着知识差距 视锥细胞有氧糖酵解如何影响视锥细胞和视网膜色素之间微妙的“代谢耦合” RP中的RPE。在这个建议中，我们假设重编程杆和锥有氧糖酵解 可以促进视锥细胞存活RP独立的潜在杆特异性基因突变。为了验证这一 根据这一假设，我们提出以下具体目标。在目标1中，我们将确定是否增强有氧运动 在一种新的遗传小鼠模型中，锥体光感受器中的糖酵解可以促进它们的存活。在目标2中，我们将 测试基因治疗通过增强小鼠有氧糖酵解来减缓感光细胞退化的潜力 RP模型和表征发生的代谢变化。最后，在目标3中，我们将评估安全性 目的2中描述的基因治疗的概况。

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.