Antisense inhibition of apoB synthesis with mipomersen reduces plasma apoC-III and apoC-III-containing lipoproteins
| Autor: | Frank M. Sacks, M. K. Wedel, Jeremy D. Furtado |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Adult
Male Apolipoprotein E medicine.medical_specialty Very low-density lipoprotein Apoc iii Adolescent Apolipoprotein B Hypercholesterolemia Mipomersen apolipoprotein C-III Oligonucleotides Phases of clinical research QD415-436 Lipoproteins VLDL Placebo Placebo group Biochemistry Chromatography Affinity Body Mass Index Young Adult Apolipoproteins E Endocrinology Internal medicine medicine Humans apolipoprotein B Triglycerides Aged Apolipoproteins B Randomized Controlled Trials as Topic apolipoprotein E biology Chemistry cholesterol Cholesterol LDL Cell Biology Middle Aged biology.protein Female lipids (amino acids peptides and proteins) atherosclerosis Patient-Oriented and Epidemiological Research Ultracentrifugation |
| Zdroj: | Journal of Lipid Research, Vol 53, Iss 4, Pp 784-791 (2012) |
| ISSN: | 0022-2275 |
| Popis: | Mipomersen, an antisense oligonucleotide that reduces hepatic production of apoB, has been shown in phase 2 studies to decrease plasma apoB, LDL cholesterol (LDL-C), and triglycerides. ApoC-III inhibits VLDL and LDL clearance, and it stimulates inflammatory responses in vascular cells. Concentrations of VLDL or LDL with apoC-III independently predict cardiovascular disease. We performed an exploratory posthoc analysis on a subset of hypercholesterolemic subjects obtained from a randomized controlled dose-ranging phase 2 study of mipomersen receiving 100, 200, or 300 mg/wk, or placebo for 13 wk (n = 8 each). ApoC-III–containing lipoproteins were isolated by immuno-affinity chromatography and ultracentrifugation. Mipomersen 200 and 300 mg/wk reduced total apoC-III from baseline by 6 mg/dl (38–42%) compared with placebo group (P < 0.01), and it reduced apoC-III in both apoB lipoproteins and HDL. Mipomersen 100, 200, and 300 mg doses reduced apoB concentration of LDL with apoC-III (27%, 38%, and 46%; P < 0.05). Mipomersen reduced apoC-III concentration in HDL. The drug had no effect on apoE concentration in total plasma and in apoB lipoproteins. In summary, antisense inhibition of apoB synthesis reduced plasma concentrations of apoC-III and apoC-III–containing lipoproteins. Lower concentrations of apoC-III and LDL with apoC-III are associated with reduced risk of coronary heart disease (CHD) in epidemiologic studies independent of traditional risk factors. |
| Databáze: | OpenAIRE |
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