title: Short locked nucleic acid antisense oligonucleotides potently reduce apolipoprotein B mRNA and serum cholesterol in mice and non-human primates.
abstract: The potency and specificity of locked nucleic acid (LNA) antisense oligonucleotides was investigated as a function of length and affinity. The oligonucleotides were designed to target apolipoprotein B (apoB) and were investigated both in vitro and in vivo. The high affinity of LNA enabled the design of short antisense oligonucleotides (12- to 13-mers) that possessed high affinity and increased potency both in vitro and in vivo compared to longer oligonucleotides. The short LNA oligonucleotides were more target specific, and they exhibited the same biodistribution and tissue half-life as longer oligonucleotides. Pharmacology studies in both mice and non-human primates were conducted with a 13-mer LNA oligonucleotide against apoB, and the data showed that repeated dosing of the 13-mer at 1-2 mg/kg/week was sufficient to provide a significant and long lasting lowering of non-high-density lipoprotein (non-HDL) cholesterol without increasing serum liver toxicity markers. The data presented here show that oligonucleotide length as a parameter needs to be considered in the design of antisense oligonucleotide and that potent short oligonucleotides with sufficient target affinity can be generated using the LNA chemistry. Conclusively, we present a 13-mer LNA oligonucleotide with therapeutic potential that produce beneficial cholesterol lowering effect in non-human primates.
authors.affiliation: Santaris Pharma A/S, Kogle Allé 6, DK-2970 Hørsholm, Denmark.
authors.forename: Ellen Marie
authors.initials: EM
authors.lastname: Straarup
authors.forename: Niels
authors.initials: N
authors.lastname: Fisker
authors.forename: Maj
authors.initials: M
authors.lastname: Hedtjärn
authors.forename: Marie W
authors.initials: MW
authors.lastname: Lindholm
authors.forename: Christoph
authors.initials: C
authors.lastname: Rosenbohm
authors.forename: Vibeke
authors.initials: V
authors.lastname: Aarup
authors.forename: Henrik Frydenlund
authors.initials: HF
authors.lastname: Hansen
authors.forename: Henrik
authors.initials: H
authors.lastname: Ørum
authors.forename: Jens B Rode
authors.initials: JB
authors.lastname: Hansen
authors.forename: Troels
authors.initials: T
authors.lastname: Koch
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism*; D001345:Autoradiography; D020137:Base Pair Mismatch; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000097:blood*; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D008810:Mice, Inbred C57BL; D009841:Oligonucleotides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D001055:Apolipoproteins B; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; C477371:locked nucleic acid; D002784:Cholesterol