Abstract: TH-OR059
Collecting Duct-Targeted Lipid Nanoparticles Deliver Pkd2 mRNA to Attenuate ADPKD
Session Information
- Genetic Diseases with a Focus on ADPKD Mechanisms, Models, and Medicines
October 22, 2026 | Location: Mile High Ballroom 4D, Convention Center
Abstract Time: 05:10 PM - 05:20 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)
Authors
- Giblin, Joshua, University of Southern California, Los Angeles, California, United States
- Chung, Eun ji, University of Southern California, Los Angeles, California, United States
Group or Team Name
- Chung Lab
Background
Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease, affecting over 12 million people worldwide. It is characterized by progressive expansion of fluid-filled cysts, leading to kidney enlargement and eventual renal failure. The only FDA-approved therapy, tolvaptan, provides limited benefit, highlighting the need for targeted therapeutic strategies. ADPKD is caused by mutations in the PKD1 or PKD2 genes, leading to the loss of functional polycystin-1 (PC1) or polycystin-2 (PC2), which, in renal tubular cells, results in heightened cell proliferation, abnormal tubular morphology, and cyst formation. Here, we develop lipid nanoparticles (LNPs) for Pkd2 mRNA delivery to collecting duct (CD) cells, the cell type primarily involved in cyst formation, to restore PC2 expression.
Methods
Lipid nanoparticles (LNPs) were functionalized with a CD-targeting peptide (CD LNPs) and the biodistribution was evaluated in an ADPKD mouse model to assess kidney targeting ability using ex vivo imaging, immunofluorescence, and flow cytometry. Therapeutic efficacy of CD LNPs loaded with Pkd2 mRNA (CD-mPkd2) was assessed in Pkd2fl/fl;Pax8-Cre mice and Pkd1fl/fl;Pax8-Cre mice to evaluate cross-genetic applicability.
Results
CD LNPs exhibited 1.8-fold higher kidney enrichment and a 2.2-fold increase in LNP-positive DBA+ collecting duct cells compared to non-targeted LNPs in cystic kidneys. Pkd2-deficient mice with established cystic disease receiving repeated CD-mPkd2 every three days at 1 mg/kg exhibited a 62% reduction in kidney weight-to-body weight ratio and kidneys 31% smaller than at baseline at endpoint, indicating regression of established disease. Repeated dosing restored renal architecture and normalized inflammatory and fibrotic gene expression. In Pkd1-deficient mice, a single dose of CD-mPkd2 reduced kidney enlargement 2.1-fold and cystic index by 48% relative to PBS controls, supporting PC2 supplementation as a genotype-independent therapeutic strategy.
Conclusion
CD-targeted LNP-mediated Pkd2 mRNA delivery reverses established cystic disease in Pkd2-deficient models, and attenuates disease progression driven by Pkd1-deficiency, establishing Pkd2 mRNA replacement as a broadly applicable therapeutic strategy for ADPKD regardless of underlying genetic mutation.
Funding
- NIDDK Support