Effects of mipomersen, an apolipoprotein B100 antisense, on lipoprotein (a) metabolism in healthy subjects
Autor: | Colleen Ngai, Marianna Pavlyha, Stephen Holleran, Santica M. Marcovina, Anastasiya Matveyenko, Wahida Karmally, Renu Nandakumar, Tiffany Thomas, Henry N. Ginsberg, Rajasekhar Ramakrishnan, Gissette Reyes-Soffer |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Adult Male medicine.medical_specialty Apolipoprotein B Mipomersen Oligonucleotides Familial hypercholesterolemia QD415-436 030204 cardiovascular system & hematology Placebo production rate Biochemistry Mass Spectrometry Oligodeoxyribonucleotides Antisense 03 medical and health sciences 0302 clinical medicine Endocrinology Internal medicine Medicine Humans fractional clearance rate biology apoB antisense treatment business.industry Cell Biology Lipoprotein(a) Metabolism Cholesterol LDL Middle Aged medicine.disease Lipid Metabolism 030104 developmental biology Apolipoprotein B-100 biology.protein Female Leucine business Patient-Oriented and Epidemiological Research Lipoprotein Chromatography Liquid |
Zdroj: | Journal of Lipid Research, Vol 59, Iss 12, Pp 2397-2402 (2018) |
Popis: | Elevated lipoprotein (a) [Lp(a)] levels increase the risk for CVD. Novel treatments that decrease LDL cholesterol (LDL-C) have also shown promise for reducing Lp(a) levels. Mipomersen, an antisense oligonucleotide that inhibits apoB synthesis, is approved for the treatment of homozygous familial hypercholesterolemia. It decreases plasma levels of LDL-C by 25% to 39% and lowers levels of Lp(a) by 21% to 39%. We examined the mechanisms for Lp(a) lowering during mipomersen treatment. We enrolled 14 healthy volunteers who received weekly placebo injections for 3 weeks followed by weekly injections of mipomersen for 7 weeks. Stable isotope kinetic studies were performed using deuterated leucine at the end of the placebo and mipomersen treatment periods. The fractional catabolic rate (FCR) of Lp(a) was determined from the enrichment of a leucine-containing peptide specific to apo(a) by LC/MS. The production rate (PR) of Lp(a) was calculated from the product of Lp(a) FCR and Lp(a) concentration (converted to pool size). In a diverse population, mipomersen reduced plasma Lp(a) levels by 21%. In the overall study group, mipomersen treatment resulted in a 27% increase in the FCR of Lp(a) with no significant change in PR. However, there was heterogeneity in the response to mipomersen therapy, and changes in both FCRs and PRs affected the degree of change in Lp(a) concentrations. Mipomersen treatment decreases Lp(a) plasma levels mainly by increasing the FCR of Lp(a), although changes in Lp(a) PR were significant predictors of reductions in Lp(a) levels in some subjects. |
Databáze: | OpenAIRE |
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