Retinitis pigmentosa (RP) is a neurodegenerative disorder that causes irreversible vision loss in over 1.5 million individuals world-wide. The genetic heterogeneity of RP necessitates a broad therapy that is able to provide treatment in a gene- and mutation- non-specific manner. In this study, we identify the therapeutic benefits of metabolic reprogramming by targeting pyruvate kinase M2 (PKM2) in a Pde6β preclinical model of RP. The genetic contributions of PKM2 inhibition in retinal degeneration were evaluated through histology and electroretinogram (ERG) followed by a statistical analysis using a linear regression model. Notably, PKM2 ablation resulted in thicker retinal layers in Pde6β-mutated mice as compared to the controls, suggesting greater photoreceptor survival. Consistent with these anatomical findings, ERG analyses revealed that the maximum b-wave is on average greater in Pkm2 knockout mice than in mice with intact Pkm2, indicating enhanced photoreceptor function. These rescue phenotypes from Pkm2 ablation in a preclinical model of RP indicate that a metabolome reprogramming may be useful in treating RP.

中文翻译：

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PKM2 消融增强了视网膜色素变性临床前模型中的视网膜功能和存活率。

色素性视网膜炎 (RP) 是一种神经退行性疾病，可导致全球超过 150 万人出现不可逆的视力丧失。RP 的遗传异质性需要能够以基因和突变非特异性方式提供治疗的广泛疗法。在这项研究中，我们通过在 RP 的 Pde6β 临床前模型中靶向丙酮酸激酶 M2 (PKM2) 来确定代谢重编程的治疗益处。通过组织学和视网膜电图 (ERG) 评估 PKM2 抑制在视网膜变性中的遗传贡献，然后使用线性回归模型进行统计分析。值得注意的是，与对照组相比，PKM2 消融导致 Pde6β 突变小鼠的视网膜层更厚，这表明光感受器存活率更高。与这些解剖发现一致，ERG 分析显示，Pkm2 敲除小鼠的最大 b 波平均高于具有完整 Pkm2 的小鼠，表明光感受器功能增强。这些来自 RP 临床前模型中 Pkm2 消融的拯救表型表明，代谢组重编程可能对治疗 RP 有用。