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Kidney Week

Abstract: PO0928

The Usefulness of Antisense Oligonucleotide Modified with Serinol Nucleic Acid for Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Tsuboi, Toshiki, Nagoya University Graduate School of Medicine Faculty of Medicine, Nagoya, Aichi, Japan
  • Ishimoto, Takuji, Nagoya Daigaku, Nagoya, Aichi, Japan
  • Imai, Kentaro, Nagoya University Graduate School of Medicine Faculty of Medicine, Nagoya, Aichi, Japan
  • Doke, Tomohito, University of Pennsylvania Department of Medicine, Philadelphia, Pennsylvania, United States
  • Kato, Noritoshi, Nagoya Daigaku, Nagoya, Aichi, Japan
  • Kamiya, Yukiko, Nagoya Daigaku, Nagoya, Aichi, Japan
  • Asanuma, Hiroyuki, Nagoya Daigaku, Nagoya, Aichi, Japan
  • Maruyama, Shoichi, Nagoya Daigaku, Nagoya, Aichi, Japan
Background

The use of nucleic acid drugs such as antisense oligonucleotides (ASOs) and siRNA has received a lot of attentions as next-generation drugs. However, the nucleic acid drugs for kidney diseases have not been put to practical use. Recently, we have newly developed the serinol nucleic acid (SNA) modified ASO which had strong nuclease resistance. In this study, we investigated the in vivo efficacy of SNA-modified ASO in mouse kidney.

Methods

Various types of PS-modified gapmer ASOs with or without SNA targeting both human and murine SGLT2 (sodium glucose cotransporter 2) were tested in the immortalized human proximal tubule epithelial cell (HK-2), and subcutaneously administered into mice. Urinary and blood glucose levels, renal function, liver function and renal SGLT2 expression were analyzed.

Results

First, we confirmed that SGLT2 ASO had enough inhibitory effects of SGLT2 expression in HK-2 cells. Next, we synthesized various types of SNA gapmer SGLT2-ASOs (SGLT2-SNA-ASO). Subcutaneous administration of SGLT2-SNA-ASO significantly suppressed renal SGLT2 mRNA and protein expressions and increased urine glucose in dose dependent manner. Those inhibitory effects of SGLT2-SNA-ASO were high and long-lasting compared with ASOs without SNA (SGLT2-ASO). No apparent kidney disfunction was observed. Mild and similar liver damages were found in both SGLT2-ASO and SGLT2-SNA-ASO groups. After subcutaneous administration of Cy5-labeled SGLT2-SNA-ASO, we observed the SGLT2-SNA-ASO accumulation in kidney, especially in renal proximal tubules, by in vivo imaging system (IVIS) and fluorescent microscope.

Conclusion

Systemic administration of SGLT2-ASO modified with novel artificial nucleic acid SNA well suppressed renal SGLT2 expression and induced urinary sugar excretion. These results indicated that ASOs modified with SNA might be applied to the development of neucleic acid drugs.