Safety evaluation of 2'-deoxy-2'-fluoro nucleotides in GalNAc-siRNA conjugates

Nucleic Acids Research
Maja M JanasMartin A Maier

Abstract

For oligonucleotide therapeutics, chemical modifications of the sugar-phosphate backbone are frequently used to confer drug-like properties. Because 2'-deoxy-2'-fluoro (2'-F) nucleotides are not known to occur naturally, their safety profile was assessed when used in revusiran and ALN-TTRSC02, two short interfering RNAs (siRNAs), of the same sequence but different chemical modification pattern and metabolic stability, conjugated to an N-acetylgalactosamine (GalNAc) ligand for targeted delivery to hepatocytes. Exposure to 2'-F-monomer metabolites was low and transient in rats and humans. In vitro, 2'-F-nucleoside 5'-triphosphates were neither inhibitors nor preferred substrates for human polymerases, and no obligate or non-obligate chain termination was observed. Modest effects on cell viability and mitochondrial DNA were observed in vitro in a subset of cell types at high concentrations of 2'-F-nucleosides, typically not attained in vivo. No apparent functional impact on mitochondria and no significant accumulation of 2'-F-monomers were observed after weekly administration of two GalNAc-siRNA conjugates in rats for ∼2 years. Taken together, the results support the conclusion that 2'-F nucleotides can be safely applied for the d...Continue Reading

References

Nov 9, 1994·Molecular and Cellular Biochemistry·T W Traut
Dec 6, 1994·Proceedings of the National Academy of Sciences of the United States of America·F C RichardsonR R Bowsher
Aug 30, 2001·The Journal of Biological Chemistry·A A JohnsonK A Johnson
Oct 4, 2003·Nature Reviews. Drug Discovery·William LewisWilliam C Copeland
Apr 20, 2004·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Russell FleischerKenneth E Sherman
Apr 6, 2007·Annual Review of Biochemistry·Maria FalkenbergClaes M Gustafsson
May 21, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Stephan A VeltkampJan H M Schellens
Feb 26, 2011·Angewandte Chemie·Muthiah ManoharanMartin Egli
Mar 13, 2012·Biochimica Et Biophysica Acta·Ligia C Gomes, Luca Scorrano
Jul 16, 2013·Orvosi hetilap·Gábor Horváth
Dec 2, 2014·Journal of the American Chemical Society·Jayaprakash K NairMuthiah Manoharan
Jul 15, 2015·Human Gene Therapy·Karin E LundinC I Edvard Smith
Aug 19, 2015·Nature Reviews. Genetics·Anders Wittrup, Judy Lieberman
Jul 9, 2016·Nucleic Acid Therapeutics·Maja M JanasScott A Barros
Oct 23, 2016·Toxicologic Pathology·Arun R PandiriThomas J Steinbach
Dec 14, 2016·The New England Journal of Medicine·Kevin FitzgeraldAmy Simon
Jan 28, 2017·Molecular Therapy : the Journal of the American Society of Gene Therapy·Tracy S ZimmermannJared Gollob
Jul 12, 2017·The New England Journal of Medicine·K John PasiMargaret V Ragni
Jan 13, 2018·Toxicological Sciences : an Official Journal of the Society of Toxicology·Amer F SalehMick D Fellows
Feb 20, 2018·Molecular Therapy : the Journal of the American Society of Gene Therapy·Donald J FosterStuart Milstein
Feb 21, 2018·Nature Communications·Maja M JanasVasant Jadhav
Jul 5, 2018·The New England Journal of Medicine·David AdamsOle B Suhr
Aug 25, 2018·Toxicologic Pathology·Maja M JanasGarvin Warner

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Citations

Jun 21, 2020·Signal Transduction and Targeted Therapy·Bo HuXing-Jie Liang
May 16, 2019·Nucleic Acid Therapeutics·Elise Malek-AdamianMasad J Damha
Jul 5, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Diane RamsdenSaeho Chong
Nov 6, 2020·Journal of Bone and Mineral Metabolism·Iván Nadir Camal RuggieriSara Feldman
Jan 30, 2021·Biochemical Pharmacology·M May ZhangXiao-Bo Zhong
Jan 14, 2020·Molecular Therapy. Nucleic Acids·Yuhua WengXing-Jie Liang
Mar 2, 2021·Biochemical Pharmacology·Christopher L BarkauKeith T Gagnon
Feb 19, 2021·The Journal of Biological Chemistry·Stanley T CrookeRosanne M Crooke
Jun 28, 2020·Molecular Therapy : the Journal of the American Society of Gene Therapy·Alexandre J DebackerNagy Habib
Aug 18, 2020·Biochemical Pharmacology·Stanley T CrookeRichard S Geary
May 23, 2021·British Journal of Clinical Pharmacology·Thomas A ForbesChengjung Lai
Aug 18, 2021·The FEBS Journal·George BibbyKehinde Ross
Oct 14, 2021·Expert Opinion on Drug Metabolism & Toxicology·Mohammad ShadidAbedelnasser Abulrob

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Methods Mentioned

BETA
transmission electron microscopy
deamination
PCR

Software Mentioned

Agilent OpenLab CDS ChemStation
Microbeta
XLfit

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