PMID- 35073217
OWN - NLM
STAT- MEDLINE
DCOM- 20220606
LR  - 20220708
IS  - 2159-3345 (Electronic)
IS  - 2159-3337 (Linking)
VI  - 32
IP  - 3
DP  - 2022 Jun
TI  - Altered Biodistribution and Hepatic Safety Profile of a Gapmer Antisense 
      Oligonucleotide Bearing Guanidine-Bridged Nucleic Acids.
PG  - 177-184
LID - 10.1089/nat.2021.0034 [doi]
AB  - Guanidine-bridged nucleic acid (GuNA) is a novel 2',4'-bridged nucleic 
      acid/locked nucleic acid (2',4'-BNA/LNA) analog containing cations that exhibit 
      strong affinity for target RNA and superior nuclease resistance. In this study, 
      Malat1 antisense oligonucleotide (ASO) bearing GuNA was evaluated for target 
      knockdown (KD) activity and tolerability. The GuNA ASO did not interfere with 
      RNase H recruitment on the target RNA/ASO heteroduplex and did show potent target 
      KD activity in a skeletal muscle-derived cell line equivalent to that of the LNA 
      ASO under gymnotic conditions, whereas almost no KD activity was observed in a 
      hepatocyte-derived cell line. The GuNA ASO exhibited potent KD activity in 
      various tissues; the KD activity in the skeletal muscle was equivalent with that 
      of the LNA ASO, but the KD activities in the liver and kidney were clearly lower 
      compared with the LNA ASO. In addition, despite the higher accumulation of the 
      GuNA ASO in the liver, levels of aspartate aminotransferase and alanine 
      aminotransferase with the GuNA ASO administration were not elevated compared with 
      those induced by the LNA ASO. Our data indicate that the GuNA ASO is tolerable 
      and exhibits unique altered pharmacological activities in comparison with the LNA 
      ASO in terms of the relative effect between liver and skeletal muscle.
FAU - Sasaki, Takashi
AU  - Sasaki T
AD  - Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 
      Fujisawa, Kanagawa, Japan.
FAU - Hirakawa, Yoko
AU  - Hirakawa Y
AD  - Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 
      Fujisawa, Kanagawa, Japan.
FAU - Yamairi, Fumiko
AU  - Yamairi F
AD  - Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 
      Fujisawa, Kanagawa, Japan.
FAU - Kurita, Takashi
AU  - Kurita T
AD  - Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 
      Fujisawa, Kanagawa, Japan.
FAU - Murahashi, Karin
AU  - Murahashi K
AD  - Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 
      Fujisawa, Kanagawa, Japan.
FAU - Nishimura, Hirokazu
AU  - Nishimura H
AD  - Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 
      Fujisawa, Kanagawa, Japan.
FAU - Iwazaki, Norihiko
AU  - Iwazaki N
AD  - Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 
      Fujisawa, Kanagawa, Japan.
FAU - Yasuhara, Hidenori
AU  - Yasuhara H
AD  - Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 
      Fujisawa, Kanagawa, Japan.
FAU - Tateoka, Takashi
AU  - Tateoka T
AD  - Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 
      Fujisawa, Kanagawa, Japan.
FAU - Ohta, Tetsuya
AU  - Ohta T
AD  - Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 
      Fujisawa, Kanagawa, Japan.
FAU - Obika, Satoshi
AU  - Obika S
AUID- ORCID: 0000-0002-6842-6812
AD  - Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, 
      Japan.
FAU - Kotera, Jun
AU  - Kotera J
AD  - Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 
      Fujisawa, Kanagawa, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220124
PL  - United States
TA  - Nucleic Acid Ther
JT  - Nucleic acid therapeutics
JID - 101562758
RN  - 0 (Guanidines)
RN  - 0 (Nucleic Acids)
RN  - 0 (Oligonucleotides, Antisense)
RN  - 63231-63-0 (RNA)
RN  - JU58VJ6Y3B (Guanidine)
SB  - IM
MH  - Guanidine/metabolism
MH  - Guanidines/metabolism
MH  - Liver/metabolism
MH  - *Nucleic Acids
MH  - *Oligonucleotides, Antisense/pharmacology
MH  - RNA/metabolism
MH  - Tissue Distribution
OTO - NOTNLM
OT  - biodistribution
OT  - extrahepatic
OT  - gapmer
OT  - guanidine-bridged nucleic acids
EDAT- 2022/01/25 06:00
MHDA- 2022/06/07 06:00
CRDT- 2022/01/24 17:14
PHST- 2022/01/25 06:00 [pubmed]
PHST- 2022/06/07 06:00 [medline]
PHST- 2022/01/24 17:14 [entrez]
AID - 10.1089/nat.2021.0034 [doi]
PST - ppublish
SO  - Nucleic Acid Ther. 2022 Jun;32(3):177-184. doi: 10.1089/nat.2021.0034. Epub 2022 
      Jan 24.