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Therapeutic microRNAs in polycystic kidney disease
Matanel Yheskel1, Vishal Patel
1Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Purpose Of Review:
microRNAs (miRNAs) are short noncoding RNAs that function as sequence-specific inhibitors of gene expression. Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic cause of end-stage kidney failure with limited treatment options. The realization that miRNA upregulation, and thus its gain-of-function, can drive the progression of ADPKD has raised the possibility that anti-miRs represent a novel drug class for this disorder.
Recent Findings:
A common set of miRNAs are aberrantly expressed in various murine models of polycystic kidney disease. In particular two miRNAs, miR-17 family and miR-21, are both upregulated in kidney cysts and promote ADPKD progression in mouse models. miR-17 rewires cyst epithelial metabolism to enhance cyst proliferation. On the other hand, miR-21 represses proapoptotic genes and thus inhibits cyst apoptosis. Importantly, an anti-miR-17 drug has advanced through preclinical ADPKD studies, whereas an anti-miR-21 drug has already cleared phase I clinical trial.
Summary:
miRNAs have emerged as new regulators of ADPKD pathogenesis. Anti-miRs represent a feasible and an entirely new class of drugs for the treatment of ADPKD.
Insights
MicroRNAs (miRNAs) drive autosomal dominant polycystic kidney disease (ADPKD) progression. Anti-miRs offer a promising new therapeutic strategy for ADPKD, with specific drugs advancing in clinical trials.
Area of Science:
- Molecular Biology
- Genetics
- Nephrology
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a leading genetic cause of kidney failure with limited treatments.
- MicroRNAs (miRNAs) are key regulators of gene expression.
- Aberrant miRNA expression contributes to ADPKD pathogenesis.
Purpose of the Study:
- To review the role of miRNAs in ADPKD.
- To explore anti-miRs as a novel therapeutic approach for ADPKD.
Main Methods:
- Analysis of miRNA expression in ADPKD models.
- Investigation of specific miRNA functions (miR-17, miR-21) in cyst development.
- Review of preclinical and clinical data for anti-miR therapies.
Main Results:
- miR-17 and miR-21 are upregulated in ADPKD kidneys and promote disease progression.
- miR-17 enhances cyst proliferation by altering metabolism.
- miR-21 inhibits apoptosis by repressing proapoptotic genes.
- Anti-miR-17 has shown promise in preclinical studies.
- Anti-miR-21 has successfully completed Phase I clinical trials.
Conclusions:
- miRNAs are critical regulators of ADPKD.
- Anti-miRs represent a feasible and novel drug class for ADPKD treatment.
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