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Article

Highly Potent GalNAc-Conjugated Tiny LNA Anti-miRNA-122 Antisense Oligonucleotides

1
Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan
2
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
3
Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 564-8565, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: Anna Angela Barba
Pharmaceutics 2021, 13(6), 817; https://doi.org/10.3390/pharmaceutics13060817
Received: 4 April 2021 / Revised: 24 May 2021 / Accepted: 28 May 2021 / Published: 31 May 2021
The development of clinically relevant anti-microRNA antisense oligonucleotides (anti-miRNA ASOs) remains a major challenge. One promising configuration of anti-miRNA ASOs called “tiny LNA (tiny Locked Nucleic Acid)” is an unusually small (~8-mer), highly chemically modified anti-miRNA ASO with high activity and specificity. Within this platform, we achieved a great enhancement of the in vivo activity of miRNA-122-targeting tiny LNA by developing a series of N-acetylgalactosamine (GalNAc)-conjugated tiny LNAs. Specifically, the median effective dose (ED50) of the most potent construct, tL-5G3, was estimated to be ~12 nmol/kg, which is ~300–500 times more potent than the original unconjugated tiny LNA. Through in vivo/ex vivo imaging studies, we have confirmed that the major advantage of GalNAc over tiny LNAs can be ascribed to the improvement of their originally poor pharmacokinetics. We also showed that the GalNAc ligand should be introduced into its 5′ terminus rather than its 3′ end via a biolabile phosphodiester bond. This result suggests that tiny LNA can unexpectedly be recognized by endogenous nucleases and is required to be digested to liberate the parent tiny LNA at an appropriate time in the body. We believe that our strategy will pave the way for the clinical application of miRNA-targeting small ASO therapy. View Full-Text
Keywords: tiny LNA; miR-122; GalNAc; Ligand-targeted drug delivery system; antisense oligonucleotide tiny LNA; miR-122; GalNAc; Ligand-targeted drug delivery system; antisense oligonucleotide
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MDPI and ACS Style

Yamamoto, T.; Mukai, Y.; Wada, F.; Terada, C.; Kayaba, Y.; Oh, K.; Yamayoshi, A.; Obika, S.; Harada–Shiba, M. Highly Potent GalNAc-Conjugated Tiny LNA Anti-miRNA-122 Antisense Oligonucleotides. Pharmaceutics 2021, 13, 817. https://doi.org/10.3390/pharmaceutics13060817

AMA Style

Yamamoto T, Mukai Y, Wada F, Terada C, Kayaba Y, Oh K, Yamayoshi A, Obika S, Harada–Shiba M. Highly Potent GalNAc-Conjugated Tiny LNA Anti-miRNA-122 Antisense Oligonucleotides. Pharmaceutics. 2021; 13(6):817. https://doi.org/10.3390/pharmaceutics13060817

Chicago/Turabian Style

Yamamoto, Tsuyoshi, Yahiro Mukai, Fumito Wada, Chisato Terada, Yukina Kayaba, Kaho Oh, Asako Yamayoshi, Satoshi Obika, and Mariko Harada–Shiba. 2021. "Highly Potent GalNAc-Conjugated Tiny LNA Anti-miRNA-122 Antisense Oligonucleotides" Pharmaceutics 13, no. 6: 817. https://doi.org/10.3390/pharmaceutics13060817

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