Antisense Oligonucleotides Targeting Lipoprotein(a)

@article{Langsted2019AntisenseOT,
  title={Antisense Oligonucleotides Targeting Lipoprotein(a)},
  author={Anne Langsted and B{\o}rge Gr{\o}nne Nordestgaard},
  journal={Current Atherosclerosis Reports},
  year={2019},
  volume={21},
  pages={1-7}
}
Purpose of ReviewHigh lipoprotein(a) levels are observationally and causally, from human genetics, associated with increased risk of cardiovascular disease including myocardial infarction and aortic valve stenosis. The European Atherosclerosis Society recommends screening for elevated lipoprotein(a) levels in high-risk patients. Different therapies have been suggested and some are used to treat elevated lipoprotein(a) levels such as niacin, PCSK9 inhibitors, and CETP inhibitors; however, to… 
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References

SHOWING 1-10 OF 62 REFERENCES
Antisense inhibition of apolipoprotein (a) to lower plasma lipoprotein (a) levels in humans
TLDR
ISIS-APO( a)Rx represents the first specific and potent drug in clinical development to lower Lp(a) levels and may be beneficial in reducing CVD events and progression of calcific aortic valve stenosis.
Mipomersen, an Antisense Oligonucleotide to Apolipoprotein B-100, Reduces Lipoprotein(a) in Various Populations With Hypercholesterolemia: Results of 4 Phase III Trials
TLDR
Mipomersen consistently and effectively reduced Lp(a), an independent, causal, genetic risk factor for cardiovascular disease and aortic stenosis, in patients with a variety of lipid abnormalities and cardiovascular risk.
Effects of mipomersen, an apolipoprotein B100 antisense, on lipoprotein (a) metabolism in healthy subjects[S]
TLDR
Heterogeneity in the response to mipomersen therapy, and changes in both FCRs and PRs affected the degree of change in Lp(a) concentrations, was examined.
Advances in lipid-lowering therapy through gene-silencing technologies
New treatment opportunities are emerging in the field of lipid-lowering therapy through gene-silencing approaches. Both antisense oligonucleotide inhibition and small interfering RNA technology aim
Lipoprotein(a) as a cardiovascular risk factor: current status
TLDR
The robust and specific association between elevated Lp(a) levels and increased cardiovascular disease (CVD)/coronary heart disease (CHD) risk, together with recent genetic findings, indicates that elevated LP(a), like elevated LDL-cholesterol, is causally related to premature CVD/CHD.
Potent Reduction of Apolipoprotein B and Low-Density Lipoprotein Cholesterol by Short-Term Administration of an Antisense Inhibitor of Apolipoprotein B
TLDR
Although injection-site reactions were common, adherence to protocol was unaffected, and Administration of an antisense oligonucleotide to human apoB resulted in a significant, prolonged, and dose-dependent reduction in apolipoprotein B and LDL-C.
Antisense oligonucleotide reduction of apoB-ameliorated atherosclerosis in LDL receptor-deficient mice[S]
TLDR
ASO-mediated suppression of apoB mRNA expression profoundly reduced plasma lipids and atherogenesis in LDLr−/− mice, leading to the hypothesis that apo B inhibition in humans with impaired LDLr activity may produce similar effects.
...
...