Kidney Week 2025 Early Program - Genetics in Clinical Nephrology-Novel Therapeutic Mechanisms for Treating Inherited Kidney Diseases

Video Transcription

Video Summary

Dr. Vishal Patel (UT Southwestern) presents autosomal dominant polycystic kidney disease (ADPKD) as a case study for “precision therapeutics” in inherited kidney disease. ADPKD is usually caused by PKD1 or PKD2 mutations; despite one defective allele, many kidney cells still express the remaining normal copy, suggesting therapies that boost that residual expression.<br /><br />Patel’s group discovered that microRNA-17 (miR-17) binds the 3’ end of PKD1 mRNA and represses it, worsening effective gene dosage. In mouse models, deleting miR-17 or editing/scrambling the miR-17 binding site on PKD1 mRNA increases PKD1 expression and reduces cyst growth, supporting a therapeutic strategy to “break the interaction.”<br /><br />They developed anti–miR-17 oligonucleotides, including a next-generation compound, farabursen, engineered to reduce toxicity seen with an earlier version. Biodistribution studies show preferential kidney delivery and, in diseased kidneys, drug localization in cyst-lining collecting ducts. In mice, treatment raises PKD1/PKD2 levels, can prevent disease onset, and in severe models can stabilize and even reverse kidney enlargement and improve renal function.<br /><br />A phase 1b/2a placebo-controlled trial measured urinary exosomal PKD1/PKD2 and MRI outcomes; results are embargoed but described as encouraging, with phase 3 planned for 2026. Patel closes by surveying other DNA/RNA/protein-targeted ADPKD programs and highlighting remaining challenges: mutation coverage, delivery, long-term safety, and assessing extra-renal effects.

Asset Subtitle

Vishal Patel

Meta Tag

Module GENE

Speaker Vishal Patel

Keywords

autosomal dominant polycystic kidney disease (ADPKD)

PKD1

PKD2

microRNA-17 (miR-17)

anti-miR oligonucleotides

farabursen

RNA target site editing

phase 1b/2a clinical trial