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Targeting miR-181a/b in retinitis pigmentosa: implications for disease progression and therapy
Bruna Lopes da Costa1,2, Peter M J Quinn3, Wen-Hsuan Wu1,3
1Jonas Children's Vision Care (JCVC) and Barbara & Donald Jonas Stem Cell Laboratory, New York-Presbyterian Hospital, New York, NY, USA.
Background:
Retinitis pigmentosa (RP) is a genetically heterogeneous group of degenerative disorders causing progressive vision loss due to photoreceptor death. RP affects other retinal cells, including the retinal pigment epithelium (RPE). MicroRNAs (miRs) are implicated in RP pathogenesis, and downregulating miR-181a/b has shown therapeutic benefit in RP mouse models by improving mitochondrial function. This study investigates the expression profile of miR-181a/b in RPE cells and the neural retina during RP disease progression. We also evaluate how miR-181a/b downregulation, by knocking out miR-181a/b-1 cluster in RPE cells, confers therapeutic efficacy in an RP mouse model and explore the mechanisms underlying this process.
Results:
Our findings reveal distinct expression profiles, with downregulated miR-181a/b in RPE cells suggesting a protective response and upregulated miR-181a/b in the neural retina indicating a role in disease progression. We found that miR-181a/b-2, encoded in a separate genomic cluster, compensates for miR-181a/b-1 ablation in RPE cells at late time points. The transient downregulation of miR-181a/b in RPE cells at post-natal week 6 (PW6) led to improved RPE morphology, retarded photoreceptor degeneration and decreased RPE aerobic glycolysis.
Conclusions:
Our study elucidates the underlying mechanisms associated with the therapeutic modulation of miR-181a/b, providing insights into the metabolic processes linked to its RPE-specific downregulation. Our data further highlights the impact of compensatory regulation between miR clusters with implications for the development of miR-based therapeutics.
Insights
Downregulating miR-181a/b in retinal pigment epithelium (RPE) cells shows therapeutic potential for retinitis pigmentosa (RP). This approach improves RPE health and slows vision loss by modulating metabolic processes.
Area of Science:
- Ophthalmology
- Genetics
- Molecular Biology
Background:
- Retinitis pigmentosa (RP) is a group of genetic disorders causing photoreceptor cell death and vision loss.
- MicroRNAs (miRs), including miR-181a/b, are involved in RP pathogenesis.
- Previous studies suggest downregulating miR-181a/b may benefit RP by enhancing mitochondrial function.
Purpose of the Study:
- To investigate miR-181a/b expression patterns in retinal pigment epithelium (RPE) and neural retina during RP progression.
- To assess the therapeutic efficacy of miR-181a/b downregulation in RPE cells using an RP mouse model.
- To explore the underlying mechanisms of miR-181a/b's therapeutic effects in RP.
Main Methods:
- Analyzing miR-181a/b expression profiles in RPE and neural retina of RP models.
- Genetically modifying RPE cells to knock out the miR-181a/b-1 cluster.
- Evaluating RPE morphology, photoreceptor survival, and metabolic activity (aerobic glycolysis) after miR-181a/b downregulation.
- Investigating compensatory miR expression from other genomic clusters.
Main Results:
- miR-181a/b showed distinct expression patterns: downregulated in RPE (protective) and upregulated in neural retina (disease-promoting).
- miR-181a/b-2 expression compensated for miR-181a/b-1 knockout in RPE cells at later stages.
- Transient miR-181a/b downregulation in RPE cells at post-natal week 6 improved RPE morphology, slowed photoreceptor degeneration, and reduced RPE aerobic glycolysis.
Conclusions:
- Therapeutic modulation of miR-181a/b in RPE cells offers a promising strategy for RP treatment.
- RPE-specific downregulation of miR-181a/b impacts metabolic processes, contributing to therapeutic efficacy.
- Understanding compensatory miR regulation is crucial for developing effective miR-based therapies for RP.
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