title: PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates.
abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a therapeutic target for the reduction of low-density lipoprotein cholesterol (LDL-C). PCSK9 increases the degradation of the LDL receptor, resulting in high LDL-C in individuals with high PCSK9 activity. Here, we show that two locked nucleic acid (LNA) antisense oligonucleotides targeting PCSK9 produce sustained reduction of LDL-C in nonhuman primates after a loading dose (20 mg/kg) and four weekly maintenance doses (5 mg/kg). PCSK9 messenger RNA (mRNA) and serum PCSK9 protein were reduced by 85% which resulted in a 50% reduction in circulating LDL-C. Serum total cholesterol (TC) levels were reduced to the same extent as LDL-C with no reduction in high-density lipoprotein levels, demonstrating a specific pharmacological effect on LDL-C. The reduction in hepatic PCSK9 mRNA correlated with liver LNA oligonucleotide content. This verified that anti-PCSK9 LNA oligonucleotides regulated LDL-C through an antisense mechanism. The compounds were well tolerated with no observed effects on toxicological parameters (liver and kidney histology, alanine aminotransferase, aspartate aminotransferase, urea, and creatinine). The pharmacologic evidence and initial safety profile of the compounds used in this study indicate that LNA antisense oligonucleotides targeting PCSK9 provide a viable therapeutic strategy and are potential complements to statins in managing high LDL-C.
authors: Santaris Pharma A/S, Hørsholm, Denmark. mwl@santaris.com
authors: Marie W
authors: MW
authors: Lindholm
authors: Joacim
authors: J
authors: Elmén
authors: Niels
authors: N
authors: Fisker
authors: Henrik F
authors: HF
authors: Hansen
authors: Robert
authors: R
authors: Persson
authors: Marianne R
authors: MR
authors: Møller
authors: Christoph
authors: C
authors: Rosenbohm
authors: Henrik
authors: H
authors: Ørum
authors: Ellen M
authors: EM
authors: Straarup
authors: Troels
authors: T
authors: Koch
mesh_terms: D000818:Animals; D008078:Cholesterol, LDL / Q000378:metabolism*; D006801:Humans; D007279:Injections, Subcutaneous; D008252:Macaca fascicularis; D008297:Male; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D009841:Oligonucleotides / Q000737:chemistry*; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism
chemical_list: D008078:Cholesterol, LDL; D020319:Oligodeoxyribonucleotides, Antisense; D009841:Oligonucleotides; C477371:locked nucleic acid; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases