Abstract
Triantennary N-acetyl galactosamine (GalNAc, GN3) and lipophilic ligands such as cholesterol and α-tocopherol conjugations dramatically improve the distribution and efficacy of second-generation antisense oligonucleotides (ASOs) in the whole liver. In this study, to characterize ligands for delivery to liver cells based on the pharmacokinetics and the efficacy, we used a LNA gapmer of ASO targeting apolipoprotein B (Apo-B) as a model compound and evaluated the amount of ASO and Apo-B mRNA in the whole liver, hepatocytes and non-parenchymal cells, and plasma total cholesterol after administration of ASO conjugated with these ligands to mice. Compared to unconjugated ASO, GN3 conjugation increased the ASO amount (7-fold) and the efficacy (more than 10-fold) in hepatocytes only and showed higher efficacy than the increase rate of the ASO amount. On the other hand, lipophilic ligand conjugations led to increased delivery (3- to 5-fold) and efficacy (5-fold) of ASO to both hepatocytes and non-parenchymal cells. GN3 and lipophilic ligands conjugations increase the AUC of ASO and the pharmacodynamic duration but did not change the half-life in the hepatocytes and np cells compared to unconjugated ASO. In the liver, the phosphodiester ...Continue Reading
References
Jan 1, 1992·Free Radical Biology & Medicine·H Kappus, A T Diplock
Jul 25, 2000·Nucleic Acids Research·M K BijsterboschM Manoharan
Oct 18, 2000·The Journal of Biological Chemistry·H TorigoeT Imanishi
Jul 4, 2002·Hematology/oncology Clinics of North America·Roger S RileyGina Romagnoli
May 9, 2003·Reproductive Biomedicine Online·Wendy L KimberMinoru S H Ko
Jun 12, 2003·Nucleic Acids Research·Arnold GrünwellerJens Kurreck
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
Sep 18, 2007·Nature Biotechnology·Christian WolfrumMarkus Stoffel
Jul 10, 2010·Nucleic Acids Research·Ellen Marie StraarupTroels Koch
Jan 15, 2011·American Journal of Physiology. Gastrointestinal and Liver Physiology·Jonathan A Fallowfield
Jul 16, 2011·Bioconjugate Chemistry·Md Rowshon AlamRudy L Juliano
Jul 14, 2012·Journal of Pharmaceutical and Biomedical Analysis·Yanyan CenHong Zhou
Dec 13, 2012·Expert Opinion on Drug Metabolism & Toxicology·Rosie Z YuRichard S Geary
Jun 19, 2013·Journal of Hepatology·Alfica SehgalKevin Fitzgerald
Aug 2, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Hai HuangAllan Tsung
Jul 6, 2014·Nucleic Acids Research·Thazha P PrakashPunit P Seth
Nov 12, 2014·Toxicologic Pathology·Kendall S Frazier
Nov 18, 2014·Nature Biotechnology·Bryan R MeadeSteven F Dowdy
Dec 2, 2014·Journal of the American Chemical Society·Jayaprakash K NairMuthiah Manoharan
Jan 15, 2015·Molecular Therapy. Nucleic Acids·Tomoko NishinaTakanori Yokota
Aug 11, 2015·Nature Communications·Kazutaka NishinaTakanori Yokota
Sep 26, 2015·PloS One·Melanie WernerRuth Broering
Dec 15, 2015·Analytical Sciences : the International Journal of the Japan Society for Analytical Chemistry·Reina OnishiHiroshi Kamimori
Citations
Apr 17, 2016·Nucleic Acids Research·Rudolph L Juliano
Jul 28, 2016·Scientific Reports·Takeshi KasuyaAkira Kugimiya
Apr 19, 2017·Nucleic Acid Therapeutics·Mado NakajimaAyahisa Watanabe
Jan 24, 2018·Nucleic Acid Therapeutics·Fumito WadaSatoshi Obika
Sep 16, 2020·Pharmacological Reviews·Ai-Ming YuMei-Juan Tu
Jul 16, 2019·Molecular Therapy : the Journal of the American Society of Gene Therapy·Youngsoo KimA Robert MacLeod
Dec 15, 2020·Bioorganic & Medicinal Chemistry·Amarnath BolluNagendra K Sharma
Dec 9, 2020·Metabolism: Clinical and Experimental·Eftaxia-Konstantina ValantiDespina Sanoudou
Feb 4, 2021·Pharmaceutics·Shintaro FumotoKoyo Nishida
Dec 20, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Manuel Hawner, Christian Ducho
Mar 17, 2021·Biopharmaceutics & Drug Disposition·Ayahisa Watanabe, Takayuki Katsube
Jun 14, 2018·Bioconjugate Chemistry·Vivek K SharmaJonathan K Watts
Sep 2, 2021·Nucleic Acid Therapeutics·Chisato TeradaTsuyoshi Yamamoto