Kidney Week 2025 Annual Meeting-Leading Edge of Therapeutic Development in Cystic Kidney Diseases

Video Transcription

Video Summary

The session “Leading-Edge and Therapeutic Development in Cystic Kidney Disease” highlighted emerging therapeutic strategies for renal ciliopathies, focusing on nephronophthisis (NPHP) and autosomal dominant polycystic kidney disease (ADPKD).<br /><br />Sophie Saunier reviewed NPHP as a pediatric, fibrotic renal ciliopathy with high genetic heterogeneity and no current treatments. Her team built complementary models (patient urine-derived renal epithelial cells, iPSC kidney organoids, and mouse models) and performed a phenotypic screen of FDA-approved drugs to restore ciliogenesis. They identified prostaglandin E1 (alprostadil) as a hit, acting largely via EP2/EP4 receptors and cAMP signaling, restoring cilia defects across multiple NPHP genotypes and improving tubular injury, fibrosis, and inflammation in Nphp1 and Nphp3 mouse models. Multi-omic analyses implicated extracellular matrix remodeling, EMT, and TNFα/NF-κB inflammatory pathways as key disease programs reversed by treatment.<br /><br />John Sayer discussed clinical challenges: NPHP often progresses to kidney failure in adolescence, creating a narrow therapeutic window and motivating earlier genetic diagnosis and registries. He presented precision approaches for CEP290/NPHP6, including antisense oligonucleotide (ASO) exon-skipping to bypass nonsense mutations and restore near-full-length protein, demonstrated in patient cells and mouse models. He also described nonsense read-through compounds (modified aminoglycosides) that can partially restore full-length transcript/protein in patient-derived cells and mice, with potential for recessive ciliopathies.<br /><br />Abigail Smith presented temporal transcriptomics in an inducible Pkd2 mouse to identify early cyst-initiation genes. Integrating bulk and single-cell data highlighted TACSTD2/TROP2 as strongly upregulated in cyst-lining epithelium in mice, human ADPKD tissue, and organoids. Preliminary tests of a TROP2-targeting antibody-drug conjugate reduced cyst area in PKD organoids, motivating mechanistic and therapeutic follow-up.<br /><br />Minji Lee overviewed siRNA therapeutics and nanoparticle delivery challenges for kidney targeting, presenting peptide-based nanomicelles that enhance renal delivery and enable combination siRNA strategies (e.g., targeting cyst growth and inflammation) in PKD models.

Asset Subtitle

Moderator(s): Whitney Besse, Ali Gharavi

Presentation(s):

Therapeutic Approaches for Nephronophthisis and Renal Ciliopathies - Sophie Saunier
Promising Drug Targets and Prospects for Clinical Trials in Renal Ciliopathies - John Sayer
Temporal Transcriptomics in PKD Models to Identify Drug Targets - Abigail Smith
siRNA Therapy Using Nanoparticles to Treat PKD - Eun ji Chung

Meta Tag

Date 11/6/2025

Pathway 1 Genetic Diseases and Development

Session ID 507323

Keywords

renal ciliopathies

cystic kidney disease

nephronophthisis (NPHP)

autosomal dominant polycystic kidney disease (ADPKD)

ciliogenesis restoration

prostaglandin E1 (alprostadil)

EP2/EP4 receptors

cAMP signaling

phenotypic drug screening

extracellular matrix remodeling

epithelial-mesenchymal transition (EMT)

TNFα/NF-κB inflammation pathway

CEP290/NPHP6 antisense oligonucleotide exon skipping

nonsense read-through compounds (modified aminoglycosides)

TACSTD2/TROP2 antibody-drug conjugate