Abstract
Development of LNA gapmers, antisense oligonucleotides used for efficient inhibition of target RNA expression, is limited by non-target mediated hepatotoxicity issues. In the present study, we investigated hepatic transcription profiles of mice administered non-toxic and toxic LNA gapmers. After repeated administration, a toxic LNA gapmer (TS-2), but not a non-toxic LNA gapmer (NTS-1), caused hepatocyte necrosis and increased serum alanine aminotransferase levels. Microarray data revealed that, in addition to gene expression patterns consistent with hepatotoxicity, 17 genes in the clathrin-mediated endocytosis (CME) pathway were altered in the TS-2 group. TS-2 significantly down-regulated myosin 1E (Myo1E), which is involved in release of clathrin-coated pits from plasma membranes. To map the earliest transcription changes associated with LNA gapmer-induced hepatotoxicity, a second microarray analysis was performed using NTS-1, TS-2, and a severely toxic LNA gapmer (HTS-3) at 8, 16, and 72 h following a single administration in mice. The only histopathological change observed was minor hepatic hypertrophy in all LNA groups across time points. NTS-1, but not 2 toxic LNA gapmers, increased immune response genes at 8 and 16 h but ...Continue Reading
References
Jan 14, 1999·Oncology·C KollmannsbergerC Bokemeyer
Oct 12, 2002·Journal of Cell Science·Dorothy I MundyGeorge S Bloom
Mar 7, 2003·Nature·Sean D Conner, Sandra L Schmid
Aug 6, 2004·Oligonucleotides·Jan Stenvang JepsenJesper Wengel
Feb 3, 2005·Nature Reviews. Molecular Cell Biology·Christine Le Roy, Jeffrey L Wrana
Jun 22, 2005·The Journal of Cell Biology·Rudy L JulianoDong Xu
Aug 8, 2006·Progress in Nucleic Acid Research and Molecular Biology·Yves PommierChristophe Redon
Sep 23, 2006·Nature Reviews. Cancer·Yves Pommier
Dec 22, 2006·Nucleic Acids Research·Eric E SwayzeC Frank Bennett
Jul 14, 2007·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Arnold Grünweller, Roland K Hartmann
Jul 17, 2007·Current Opinion in Cell Biology·Ernst J Ungewickell, Lars Hinrichsen
Apr 11, 2008·Journal of Gastroenterology and Hepatology·Carol A CaseyBenita L McVicker
May 26, 2009·Biochemical Pharmacology·David J FernandezPamela L Tuma
Oct 9, 2009·Toxicological Sciences : an Official Journal of the Society of Toxicology·Daphna LaifenfeldMichael P Lawton
Jan 9, 2010·Annual Review of Pharmacology and Toxicology·C Frank Bennett, Eric E Swayze
Jul 10, 2010·Nucleic Acids Research·Ellen Marie StraarupTroels Koch
Feb 25, 2011·Nucleic Acids Research·Erich KollerC Frank Bennett
Jun 2, 2011·Nature Reviews. Drug Discovery·Dan Jones
Jul 23, 2011·Nature Reviews. Molecular Cell Biology·Harvey T McMahon, Emmanuel Boucrot
Nov 11, 2011·PloS One·Ahmed E EnayetallahClaire M Steppan
Feb 23, 2012·Bioinformatics·Leonid ChindelevitchEnoch S Huang
Mar 2, 2012·Clinical and Translational Science·Kyle J DiehlChristopher A DeSouza
Apr 17, 2012·The Journal of Pharmacology and Experimental Therapeutics·Sebastien A BurelScott P Henry
Jun 8, 2012·Molecular Biology of the Cell·Jackie ChengDavid G Drubin
Aug 3, 2012·Nucleic Acid Therapeutics·Robert StantonRobert Dullea
Oct 18, 2012·Annual Review of Pathology·Lyndsay Murrow, Jayanta Debnath
Jan 25, 2013·Molecular Therapy. Nucleic Acids·Arthur M Krieg
Sep 10, 2013·BMC Pharmacology & Toxicology·Ahmed E EnayetallahMathew T Pletcher
Citations
Jul 12, 2014·Nature Reviews. Drug Discovery·Zhonghan Li, Tariq M Rana
Jan 23, 2016·Frontiers in Genetics·Brandon J WaltersIva B Zovkic
Dec 9, 2015·Nucleic Acid Therapeutics·Satoko Kakiuchi-KiyotaNagappan Mathialagan
Dec 19, 2015·Bioorganic & Medicinal Chemistry·Tsuyoshi YamamotoSatoshi Obika
Oct 20, 2015·Epigenomics·Peter O BrookAndrew L Durham
Nov 11, 2015·Nucleic Acids Research·Sebastien A BurelScott P Henry
Aug 11, 2015·Nature Communications·Kazutaka NishinaTakanori Yokota
Jul 28, 2016·Scientific Reports·Takeshi KasuyaAkira Kugimiya
Jul 20, 2016·Journal of Medicinal Chemistry·W Brad Wan, Punit P Seth
Sep 7, 2016·Pharmacology & Therapeutics·Danielle L Michell, Kasey C Vickers
Apr 21, 2017·Nucleic Acids Research·Peter H HagedornMorten Lindow
Nov 12, 2014·Toxicologic Pathology·Kendall S Frazier
Oct 21, 2015·Nutrition & Diabetes·W R LagorD J Rader
May 1, 2019·Nature Biotechnology·Wen ShenStanley T Crooke
Mar 16, 2017·EMBO Molecular Medicine·Caroline GodfreyVirginia Arechavala-Gomeza
Apr 30, 2019·Nucleic Acids Research·Michael T MigawaPunit P Seth
Oct 22, 2019·Stem Cells Translational Medicine·Patricia García-GarcíaFlor María Pérez-Campo
May 12, 2015·Current Opinion in Allergy and Clinical Immunology·Mark M PerryKian Fan Chung
Jul 29, 2016·Journal of Atherosclerosis and Thrombosis·Tsuyoshi YamamotoMariko Harada-Shiba
Aug 9, 2020·Medicinal Research Reviews·Dunhui LiSteve D Wilton
Apr 15, 2017·Basic Research in Cardiology·Claudio SchuolerMatthias Brock
Jun 27, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Alfonso Soler-BistuéMarcelo E Tolmasky
Mar 16, 2017·Environmental and Molecular Mutagenesis·Melanie GuérardTessier Yann
May 24, 2018·Nucleic Acids Research·Peter H HagedornMorten Lindow
Aug 25, 2018·Toxicologic Pathology·Maja M JanasGarvin Warner
Dec 9, 2020·Proceedings of the National Academy of Sciences of the United States of America·Olga A PatutinaMarina A Zenkova
Dec 29, 2020·Frontiers in Genetics·Nan ZhangTetsuo Ashizawa
Sep 20, 2019·Microorganisms·Shunbin Xu, Linda D Hazlett
Sep 18, 2017·Molecular Therapy. Nucleic Acids·Piotr J KamolaJoel D Parry
May 8, 2021·Archives of Toxicology·Tom T G NieskensAnna-Karin Sjögren
Aug 31, 2017·ACS Chemical Biology·Kassie S ManningThomas A Cooper
Dec 28, 2019·Molecular Therapy. Nucleic Acids·Philippine AupyAurélie Goyenvalle