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Kidney Week

Abstract: SA-PO550

Kidney-Targeting Mesoscale Nanoparticles for Delivery of Gene Therapy in CKD

Session Information

  • Bioengineering
    October 26, 2024 | Location: Exhibit Hall, Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Bioengineering

  • 400 Bioengineering

Authors

  • Jaimes, Edgar A., Memorial Sloan Kettering Cancer Center, New York, New York, United States
  • Vasylaki, Anastasiia, The City College of New York, New York, New York, United States
  • Roach, Arantxa, The City College of New York, New York, New York, United States
  • Ghosh, Pratyusha, The City College of New York, New York, New York, United States
  • Baltaci, Melis, Memorial Sloan Kettering Cancer Center, New York, New York, United States
  • Williams, Ryan, The City College of New York, New York, New York, United States
Background

Despite the rapidly increasing number of gene therapies being introduced into clinical practice, no such treatment is available for kidney diseases. One of the major obstacles in gene therapy implementation is the difficulty in delivering biological molecules to the disease site due to their easily degradable nature, immunogenicity, and inability to permeate through cell membranes. Here, we developed a polymer nanoparticle gene delivery system for chronic kidney disease.

Methods

We optimized the formulation of kidney-targeted polymeric mesoscale nanoparticles (MNPs) to maximize the encapsulation of siRNA and mRNA gene therapies for kidney diseases. Specifically, we formulated MNPs from poly-lactic-co-glycolic polyethylene glycol di-block (PLGA-PEG) polymer. This process was optimized for loading of a luciferase reporter mRNA, which was evaluated for renal delivery and protein expression in hairless mice. Separately, it was optimized for loading of cytokine-specific siRNA (IL-6, IL-1B, and TNFa), which were evaluated for therapeutic efficacy in a mouse model of unilateral uretral obstruction (UUO) and a rat model of Dahl Salt-Sensitive (DSS) salt-induced hypertension. We evaluated blood and urine markers of renal function in both models, as well as performed histology.

Results

We optimized mesoscale nanoparticles for maximal siRNA and mRNA therapy loading while maintaining a 300 – 400 nm polymeric MNP diameter. In healthy immunocompetent hairless mice, we found that MNPs specifically localize to the kidneys and deliver functional luciferase reporter mRNA via in vivo bioluminescence imaging. In both mouse and rat chronic kidney disease models (UUO and DSS, respectively), we administered inflammatory cytokine-silencing siRNA-loaded MNPs. These studies demonstrated substantial therapeutic efficacy and reduction of inflammation from kidney-targeted siRNA delivery as measured by renal fibrosis and injury markers. MNPs localize to the kidneys with up to 26-fold specificity compared to other organs with little to no off-target delivery or toxicity.

Conclusion

We anticipate further pre-clinical development of both mRNA and siRNA-targeted delivery to the kidneys for chronic kidney diseases will result in a highly specific novel therapy with minimal off-target effects for CKD and other renal diseases.

Funding

  • Other NIH Support