Abstract: FR-PO0308
Development of Novel Gene Therapy Approaches for the Treatment of Kidney Fibrosis in Diabetic Kidney Disease
Session Information
- Diabetic Kidney Disease: Basic and Translational Science Advances - 1
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Pontrelli, Paola, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Squiccimarro, Elena, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- di Bari, Ighli, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Conserva, Francesca, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Sclavo, Giorgia, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Stasi, Alessandra, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Franzin, Rossana, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Fiorentino, Marco, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Sallustio, Fabio, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Denora, Nunzio, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Iacobazzi, Rosa Maria, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Arduino, Ilaria, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Fondaj, Dafina, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Federici, Massimo, Universita degli Studi di Roma Tor Vergata, Rome, Lazio, Italy
- Casagrande, Viviana, Universita degli Studi di Roma Tor Vergata, Rome, Lazio, Italy
- Menghini, Rossella, Universita degli Studi di Roma Tor Vergata, Rome, Lazio, Italy
- Gesualdo, Loreto, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
Background
Diabetic kidney disease (DKD) is an important complication of type 2 diabetes and the main cause of progression to end-stage renal disease. Among the molecular mechanisms underlying DKD, lysine-63 ubiquitination, regulated by the UBE2v1 gene and miR-27b-3p, plays a key role in driving tubulointerstitial fibrosis. The aim of this study was to develop innovative gene therapy approaches to selectively modulate this pathway.
Methods
To this purpose, we engineered lipid nanoparticles (LNPs) composed of ionizable cationic lipids, cholesterol, helper lipids, and PEG-lipids. These LNPs were labeled with rhodamine and loaded with either a siRNA targeting UBE2v1 or a miRNA mimic of miR-27b-3p.
Results
In vitro fluorescence microscopy analysis confirmed that rhodamine-labeled LNPs effectively entered in HK2 renal tubular cells and localized within the cytoplasm. Furthermore, the LNPs exhibited no cytotoxicity, demonstrating biocompatibility across a concentration range of 15–70 nM. Delivery efficacy was validated by a significant downregulation of UBE2v1 in transfected cells under hyperglycemic conditions, both at the transcriptional level (p<10-9 for siRNA-LNPs; p<0.05 for miRNA-LNPs) and translational level (p<0.0001 for siRNA-LNPs; p<0.05 for miRNA-LNPs).
The nanoparticle systems were also tested in vivo in diabetic DBA2J mice. Analysis of various administration routes (intraperitoneal, subcutaneous, intravenous, retro-orbital) and time points revealed that intraperitoneal injection ensured the most efficient renal delivery of fluorescent LNPs. Histological evaluations showed no significant inflammatory infiltration or tissue alterations in treated animals. Finally, in vivo treatment with siRNA-LNPs (three intraperitoneal injections on alternate days at 1 mg/kg/day) resulted in a significant reduction of renal UBE2v1 expression (p<0.05).
Conclusion
In conclusion, our findings support the potential of gene therapy as a novel strategy to counteract fibrosis progression in diabetic kidney disease by targeting lysine-63 ubiquitination. Further studies will be required to validate these approaches in clinical trials.
Funding
- Government Support – Non-U.S.