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PKM2 ablation enhanced retinal function and survival in a preclinical model of retinitis pigmentosa
Ethan Zhang1, Joseph Ryu1, Sarah R Levi1
1Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory, Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA.
Abstract:
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.
Insights
Targeting pyruvate kinase M2 (PKM2) through metabolic reprogramming shows therapeutic benefits for retinitis pigmentosa (RP). PKM2 inhibition preserved photoreceptor cells and enhanced vision in a preclinical RP model.
Area of Science:
- Ophthalmology
- Neuroscience
- Metabolic Biology
Background:
- Retinitis pigmentosa (RP) is a leading cause of irreversible blindness affecting over 1.5 million people globally.
- The genetic diversity of RP presents a challenge for developing effective, gene-independent therapies.
- Metabolic dysregulation is increasingly recognized as a factor in neurodegenerative diseases.
Purpose of the Study:
- To investigate the therapeutic potential of targeting pyruvate kinase M2 (PKM2) for retinitis pigmentosa (RP).
- To evaluate the effects of PKM2 inhibition on photoreceptor survival and function in a preclinical RP model.
Main Methods:
- Utilized a Pde6β preclinical model of RP.
- Assessed therapeutic benefits through histological analysis of retinal layers and electroretinogram (ERG) recordings.
- Employed statistical analysis, including linear regression, to evaluate genetic contributions.
Main Results:
- PKM2 ablation led to thicker retinal layers in Pde6β-mutated mice, indicating increased photoreceptor survival.
- ERG analyses demonstrated enhanced photoreceptor function, with greater maximum b-wave amplitude in Pkm2 knockout mice.
- These findings suggest a protective role of PKM2 inhibition against retinal degeneration.
Conclusions:
- Metabolic reprogramming by targeting PKM2 offers a promising, gene-non-specific therapeutic strategy for RP.
- PKM2 inhibition demonstrates significant rescue phenotypes in a preclinical model, supporting its potential clinical utility.
- Further research into metabolome reprogramming could lead to novel treatments for RP and other neurodegenerative vision disorders.
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