In vivo efficacy and safety of systemically administered serinol nucleic acid-modified antisense oligonucleotides in mouse kidney
Nucleic acid medicine encompassing antisense oligonucleotides (ASOs) has garnered interest as a potential avenue for next-generation therapeutics. However, their therapeutic application has been constrained by challenges such as instability, off-target effects, delivery issues, and immunogenic respo...
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Elsevier
2025-03-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253124002749 |
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| author | Toshiki Tsuboi Keita Hattori Takuji Ishimoto Kentaro Imai Tomohito Doke Junichiro Hagita Jumpei Ariyoshi Kazuhiro Furuhashi Noritoshi Kato Yasuhiko Ito Yukiko Kamiya Hiroyuki Asanuma Shoichi Maruyama |
| author_facet | Toshiki Tsuboi Keita Hattori Takuji Ishimoto Kentaro Imai Tomohito Doke Junichiro Hagita Jumpei Ariyoshi Kazuhiro Furuhashi Noritoshi Kato Yasuhiko Ito Yukiko Kamiya Hiroyuki Asanuma Shoichi Maruyama |
| author_sort | Toshiki Tsuboi |
| collection | DOAJ |
| description | Nucleic acid medicine encompassing antisense oligonucleotides (ASOs) has garnered interest as a potential avenue for next-generation therapeutics. However, their therapeutic application has been constrained by challenges such as instability, off-target effects, delivery issues, and immunogenic responses. Furthermore, their practical utility in treating kidney diseases remains unrealized. Recently, we developed a serinol nucleic acid-modified ASO (SNA-ASO) that exhibits significant nuclease resistance. In this study, we evaluated the in vivo efficacy of SNA-ASOs in mouse kidney. We subcutaneously administered various types of phosphorothioate-modified gapmer ASOs with SNA or 2′-O-methoxyethyl (2′-MOE) modifications (MOE-ASO) targeting sodium glucose cotransporter 2 (SGLT2) in mice. The subcutaneous administration of SGLT2-SNA-ASO led to a dose-dependent reduction in renal SGLT2 expression and subsequent glucosuria. The inhibitory effects of SGLT2-SNA-ASO were more potent and prolonged than those of ASOs without SNA. Moreover, SGLT2-SNA-ASO did not cause severe liver damage, unlike SGLT2-MOE-ASO. The administration of Cy5-labeled-ASOs demonstrated an early increase in renal uptake, particularly in the renal proximal tubules, when modified with SNA. In conclusion, systemic administration of SGLT2-ASO modified with the artificial nucleic acid SNA effectively suppressed renal SGLT2 expression and induced urinary glucose excretion. These results suggest that SNA-modified ASOs show potential for application in developing nucleic acid therapeutics. |
| format | Article |
| id | doaj-art-1f408c1736f346cd9140efe0037331d9 |
| institution | Kabale University |
| issn | 2162-2531 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj-art-1f408c1736f346cd9140efe0037331d92025-01-04T04:56:15ZengElsevierMolecular Therapy: Nucleic Acids2162-25312025-03-01361102387In vivo efficacy and safety of systemically administered serinol nucleic acid-modified antisense oligonucleotides in mouse kidneyToshiki Tsuboi0Keita Hattori1Takuji Ishimoto2Kentaro Imai3Tomohito Doke4Junichiro Hagita5Jumpei Ariyoshi6Kazuhiro Furuhashi7Noritoshi Kato8Yasuhiko Ito9Yukiko Kamiya10Hiroyuki Asanuma11Shoichi Maruyama12Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Nephrology, Yokkaichi Municipal Hospital, Yokkaichi, JapanDepartment of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan; Corresponding author: Takuji Ishimoto, Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan.Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, JapanDepartment of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, JapanLaboratory of Bioanalytical Chemistry, Kobe Pharmaceutical University, Kobe, JapanDepartment of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Nephrology and Rheumatology, Aichi Medical University, Nagakute, JapanDepartment of Biomolecular Engineering, Nagoya University Graduate School of Engineering, Nagoya, Japan; Laboratory of Bioanalytical Chemistry, Kobe Pharmaceutical University, Kobe, JapanDepartment of Biomolecular Engineering, Nagoya University Graduate School of Engineering, Nagoya, JapanDepartment of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, JapanNucleic acid medicine encompassing antisense oligonucleotides (ASOs) has garnered interest as a potential avenue for next-generation therapeutics. However, their therapeutic application has been constrained by challenges such as instability, off-target effects, delivery issues, and immunogenic responses. Furthermore, their practical utility in treating kidney diseases remains unrealized. Recently, we developed a serinol nucleic acid-modified ASO (SNA-ASO) that exhibits significant nuclease resistance. In this study, we evaluated the in vivo efficacy of SNA-ASOs in mouse kidney. We subcutaneously administered various types of phosphorothioate-modified gapmer ASOs with SNA or 2′-O-methoxyethyl (2′-MOE) modifications (MOE-ASO) targeting sodium glucose cotransporter 2 (SGLT2) in mice. The subcutaneous administration of SGLT2-SNA-ASO led to a dose-dependent reduction in renal SGLT2 expression and subsequent glucosuria. The inhibitory effects of SGLT2-SNA-ASO were more potent and prolonged than those of ASOs without SNA. Moreover, SGLT2-SNA-ASO did not cause severe liver damage, unlike SGLT2-MOE-ASO. The administration of Cy5-labeled-ASOs demonstrated an early increase in renal uptake, particularly in the renal proximal tubules, when modified with SNA. In conclusion, systemic administration of SGLT2-ASO modified with the artificial nucleic acid SNA effectively suppressed renal SGLT2 expression and induced urinary glucose excretion. These results suggest that SNA-modified ASOs show potential for application in developing nucleic acid therapeutics.http://www.sciencedirect.com/science/article/pii/S2162253124002749MT: Oligonucleotides: Therapies and Applicationsantisense oligonucleotideASOserinol nucleic acidSNAserinol nucleic acid-modified antisense oligonucleotide |
| spellingShingle | Toshiki Tsuboi Keita Hattori Takuji Ishimoto Kentaro Imai Tomohito Doke Junichiro Hagita Jumpei Ariyoshi Kazuhiro Furuhashi Noritoshi Kato Yasuhiko Ito Yukiko Kamiya Hiroyuki Asanuma Shoichi Maruyama In vivo efficacy and safety of systemically administered serinol nucleic acid-modified antisense oligonucleotides in mouse kidney Molecular Therapy: Nucleic Acids MT: Oligonucleotides: Therapies and Applications antisense oligonucleotide ASO serinol nucleic acid SNA serinol nucleic acid-modified antisense oligonucleotide |
| title | In vivo efficacy and safety of systemically administered serinol nucleic acid-modified antisense oligonucleotides in mouse kidney |
| title_full | In vivo efficacy and safety of systemically administered serinol nucleic acid-modified antisense oligonucleotides in mouse kidney |
| title_fullStr | In vivo efficacy and safety of systemically administered serinol nucleic acid-modified antisense oligonucleotides in mouse kidney |
| title_full_unstemmed | In vivo efficacy and safety of systemically administered serinol nucleic acid-modified antisense oligonucleotides in mouse kidney |
| title_short | In vivo efficacy and safety of systemically administered serinol nucleic acid-modified antisense oligonucleotides in mouse kidney |
| title_sort | in vivo efficacy and safety of systemically administered serinol nucleic acid modified antisense oligonucleotides in mouse kidney |
| topic | MT: Oligonucleotides: Therapies and Applications antisense oligonucleotide ASO serinol nucleic acid SNA serinol nucleic acid-modified antisense oligonucleotide |
| url | http://www.sciencedirect.com/science/article/pii/S2162253124002749 |
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