Kidney Week

Abstract: PO1227

Efficacy and Adverse Effects of a Novel Mesoscale Nanoparticle-Guided Sirolimus Delivery Strategy in a Pkhd1PCK Rat Model

Session Information

• Cystic Kidney Disease - I
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1001 Genetic Diseases of the Kidneys: Cystic

Authors

• Mrug, Michal, The University of Alabama at Birmingham, Birmingham, Alabama, United States

Michal Mrug, MD

• Heller, Daniel A., Memorial Sloan Kettering Cancer Center, New York, New York, United States

Daniel A. Heller,

• Kapadia, Chintan H., Goldilocks Therapeutics, New York, New York, United States

Chintan H. Kapadia,

• Williams, Ryan, The City College of New York, New York, New York, United States

Ryan Williams,

• Chumley, Phillip H., The University of Alabama at Birmingham, Birmingham, Alabama, United States

Phillip H. Chumley,

• Mullen, Sean, The University of Alabama at Birmingham, Birmingham, Alabama, United States

Sean Mullen,

• Roye, Ronald E., The University of Alabama at Birmingham, Birmingham, Alabama, United States

Ronald E. Roye,

• Rezonzew, Gabriel, The University of Alabama at Birmingham, Birmingham, Alabama, United States

Gabriel Rezonzew,

• Zhou, Juling, The University of Alabama at Birmingham, Birmingham, Alabama, United States

Juling Zhou,

• Jaimes, Edgar A., Memorial Sloan Kettering Cancer Center, New York, New York, United States

Edgar A. Jaimes,

Background

Pre-clinical studies have shown that mTOR inhibition attenuated renal cystic disease progression but it did not improve outcomes in patients with autosomal dominant polycystic kidney disease (ADPKD). This was attributed to the dose limitations in humans due to mTOR inhibitor toxicity. To increase the mTOR inhibition efficacy and reduce its toxicity in renal cystic diseases, we studied mesoscale nanoparticle (MNP)-guided delivery of an mTOR inhibitor, sirolimus (MNP-sirolimus), in Pkhd1^PCK/PCK rats. We used our recently developed MNPs that selectively and with high affinity target the renal tubular epithelium.

Methods

We synthesized Empty-MNPs or MNP-sirolimus and used them in an experiment that resembles seminal pre-clinical studies of tolvaptan, the only FDA-approved ADPKD therapeutic. Newly outbred Pkhd1^PCK/PCK rat males were divided into 3 groups (each N= 8-9) and treated for 8 weeks (p22 to p77) with: Empty-MNP (50 mg/kg IV q96 hours), Free-sirolimus (0.15 mg/kg IV q48 hours) and MNP-sirolimus (50 mg/kg IV equivalent to 0.3 mg/kg sirolimus q96 hours). Pre- and post-treatment cyst volumes were assessed by MRI at p21 and p78.

Results

The MNP-sirolimus or Free-sirolimus both inhibited renal mTOR activity in Pkhd1^PCK/PCK rats. The mean pS6/total S6 ratios were: 7.9 for MNP-Sirolimus vs 19.1 for Free-Rapa and 105.1 for Empty-MNP (p<0.001) while total S6 levels did not differ (p=0.806). Similarly, an 8-week mTOR inhibition reduced mean renal cyst volumes: 39.9 mm³ for MNP-sirolimus vs 59.3 mm³ for Free-sirolimus vs 148.4 mm³ for Empty-MNP (overall p=0.011). However, in pairwise comparison with Empty-MNP treatment, this difference was significant only for MNP-sirolimus (p=0.017) while for Free-sirolimus, the significance was marginal (p=0.052). The pre-treatment renal cyst volumes at 3 weeks were not significantly different (p=0.772). Among side effects, mTOR inhibition reduced body and heart weights (p<0.001 and p=0.004); in both cases, their averages were less severely reduced in MNP-Sirolimus as compared to Free-sirolimus treated rats.

Conclusion

Together, our studies support the concept that a novel MNP-guided sirolimus delivery increases renal mTOR inhibition and therapeutic efficacy in renal cystic diseases, while reducing systemic toxicity.

Funding

• NIDDK Support