ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005


The Latest on Twitter

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

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Natoli, Thomas A., Sanofi, Framingham, Massachusetts, United States
  • Smith, Laurie A., Sanofi, Framingham, Massachusetts, United States
  • Kaplan, Nathan, Sanofi, Framingham, Massachusetts, United States
  • Rogers, Kelly A., Genzyme Corporation, Framingham, Massachusetts, United States
  • Ying, Xiaoyou, Sanofi, Framingham, Massachusetts, United States
  • Qiu, Weiliang, Sanofi Genzyme, Framingham, Massachusetts, United States
  • Beskrovnaya, Oxana, Sanofi Genzyme, Framingham, Massachusetts, United States

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 Pkd1tm1.1Pcha 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.


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.


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.


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


  • Commercial Support