Kidney Week

Abstract: FR-OR010

Dissection of the Therapeutic Effect of Glucosylceramide Synthase Inhibition on Polycystic Kidney Disease Progression in Adult Pkd1 RC/RC Mice

Session Information

• Advances in PKD: From Omics to Therapeutics
  November 08, 2019 | Location: 143, Walter E. Washington Convention Center
  Abstract Time: 06:18 PM - 06:30 PM

Category: Genetic Diseases of the Kidneys

• 1001 Genetic Diseases of the Kidneys: Cystic

Authors

• Natoli, Thomas A., Sanofi, Framingham, Massachusetts, United States

Thomas A. Natoli, PhD

• Smith, Laurie A., Sanofi, Framingham, Massachusetts, United States

Laurie A. Smith,

• Kaplan, Nathan, Sanofi, Framingham, Massachusetts, United States

Nathan Kaplan,

• Rogers, Kelly A., Genzyme Corporation, Framingham, Massachusetts, United States

Kelly A. Rogers,

• Ying, Xiaoyou, Sanofi, Framingham, Massachusetts, United States

Xiaoyou Ying,

• Qiu, Weiliang, Sanofi Genzyme, Framingham, Massachusetts, United States

Weiliang Qiu,

• Beskrovnaya, Oxana, Sanofi Genzyme, Framingham, Massachusetts, United States

Oxana Beskrovnaya,

Background

Glucosylceramide synthase inhibitors (GCSi) have been shown to inhibit cystogenesis in multiple preclinical models of PKD. To determine how GCSi treatment impacts kidney disease progression in an adult, orthologous mouse model of ADPKD over a sustained period, we have treated homozygous Pkd1^tm1.1Pcha mice carrying the R3277C mutation (Pkd1 RC/RC) with a GCSi for one year. To assess the impact on liver cyst formation, we treated Pkd1 conditional knockout (cKO) mice with a GCSi from 7-36 days of age.

Methods

Pkd1 RC/RC mice were randomized into vehicle or GCSi treatment groups at 4 months of age. Genz-667161 was delivered ad libitum in feed (0.03% w/w) until sacrifice at 16 months of age. Periodic high-field (7T) Magnetic Resonance Imaging (MRI) analysis was used to determine total kidney volume (TKV) changes over time. Pkd1 cKO mice were treated with the GCSi Genz-123346 from 7-36 days of age. Kidneys and livers were isolated for histological analysis at the end of study for both Pkd1 RC/RC and cKO mice.

Results

Kidney volume in Pkd1 RC/RC mice was increased compared to wild-type mice prior to treatment at 4 months of age. GCSi treatment reduced the TKV of Pkd1 RC/RC mice within 1 month of treatment; in contrast, vehicle treated Pkd1 RC/RC mice showed a gradual increase in TKV over the same time period. This anti-cystic effect was observed for the duration of the study. At sacrifice, kidney/body weight ratio was significantly decreased in GCSi-treated animals compared to controls. Liver cyst growth was reduced in GCSi treated animals compared to vehicle controls.

Conclusion

GCSi treatment inhibits kidney and liver cyst growth in Pkd1-linked mouse models. Moreover, GCSis have a sustained effect on kidney cyst growth.

Funding

• Commercial Support –