Kidney Week

Abstract: TH-PO460

Enteropeptidase Inhibitor SCO-792 Ameliorates Disease Progression in a Mouse Model of Autosomal Dominant Polycystic Kidney Disease

Session Information

• Cystic Kidney Diseases: Clinical Assessment and Therapeutic Directions
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Kawamura, Takuro, Department of Rheumatology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan

Takuro Kawamura, MD

• Hattanda, Fumihiko, Department of Rheumatology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan

Fumihiko Hattanda

• Takenaka, Shun, Department of Rheumatology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan

Shun Takenaka, DrMed

• Watanabe-Kusunoki, Kanako, Department of Rheumatology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan

Kanako Watanabe-Kusunoki, MD

• Sugama, Jun, SCOHIA PHARMA, Inc, Fujisawa, Japan

Jun Sugama, PhD

• Moritoh, Yusuke, SCOHIA PHARMA, Inc, Fujisawa, Japan

Yusuke Moritoh, PhD

• Watanabe, Masanori, SCOHIA PHARMA, Inc, Fujisawa, Japan

Masanori Watanabe

• Nakazawa, Daigo, Department of Rheumatology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan

Daigo Nakazawa, MD, PhD

• Atsumi, Tatsuya, Department of Rheumatology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan

Tatsuya Atsumi, APN

• Nishio, Saori, Department of Hemodialysis and Apheresis, Hokkaido University Hospital, Sapporo, Japan

Saori Nishio, MD, PhD

Background

Excess branched-chain amino acids activate the mammalian target of the rapamycin (mTOR) pathway, leading to disease progression of autosomal dominant polycystic kidney disease (ADPKD). Enteropeptidase inhibitor SCO-792 decreases amino acid absorption by inhibiting the digestive enzyme that converts protein to amino acids. This study aims to investigate the effects of SCO-792 on ADPKD model mice.

Methods

Pkd1 gene conditional knockout mice (Pkd1^flox/flox Mx-1-Cre mice) were randomly assigned to a vehicle group and a group treated with SCO-792 (SCO group). The vehicle group was fed a normal diet from day 28. The SCO group was fed a diet containing 0.003% (w/w) SCO-792 starting on day 28, and the dose level was increased to 0.01% from day 42. All mice were sacrificed at 98 days of age. We analyzed the phenotype of cystic kidneys by measuring kidney/body weight ratio (KW/BW) and kidney cystic index (CI), defined as the percentage of areas occupied by cysts. Additionally, we performed immunofluorescence staining of Ki-67 for kidney tissue to evaluate cell proliferation. We also conducted western blotting of the signaling pathway of cyst growth by using the whole kidney protein.

Results

Until day 42, there was no significant difference in body weight between the two groups. Following the administration of 0.01% SCO-792, the SCO group exhibited a significant reduction in body weight compared to the vehicle group. KW/BW tended to be lower in the SCO group than in the vehicle group. CI of the SCO group was significantly lower than the vehicle group (28.2 ± 10.8% vs 42.8 ± 13.6%, p=0.037). Serum urea nitrogen levels in the SCO group were significantly lower than the in vehicle group. The SCO group showed a significant decrease in Ki-67-positive cells in kidney compared to the vehicle group. In western blotting, phosphorylated-S6 protein was significantly downregulated in the SCO group compared to the vehicle group.

Conclusion

In the ADPKD mouse model, SCO-792 ameliorates renal cyst growth and kidney function decline by inhibiting the mTOR pathway activation.

Funding

• Commercial Support – SCOHIA PHARMA, Inc