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Intrathecal Delivery of Antisense Oligonucleotides in the Rat Central Nervous System
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Antisense Oligonucleotides Targeting Lipoprotein(a).

Anne Langsted1,2,3, Børge G Nordestgaard4,5,6

  • 1Department of Clinical Biochemistry, Herlev Gentofte Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730, Herlev, Denmark. anne.langsted.01@regionh.dk.

Current Atherosclerosis Reports
|May 22, 2019
PubMed
Summary

High lipoprotein(a) levels increase cardiovascular risk. New antisense oligonucleotides show promise in lowering these levels, but clinical trials are needed to confirm reduced cardiovascular disease risk.

Keywords:
AKCEA-APO(a)-LRxApolipoprotein BApolipoprotein(a)Mipomersen

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Area of Science:

  • Cardiovascular Medicine
  • Genetics
  • Pharmacology

Background:

  • Elevated lipoprotein(a) is a significant risk factor for cardiovascular diseases like heart attack and aortic valve stenosis.
  • Genetic studies confirm a causal link between high lipoprotein(a) and increased cardiovascular disease (CVD) risk.
  • Current guidelines recommend screening for high lipoprotein(a) in high-risk individuals.

Purpose of the Study:

  • To review current and emerging therapies for lowering elevated lipoprotein(a) levels.
  • To assess the efficacy of novel antisense oligonucleotide therapies in reducing lipoprotein(a).
  • To highlight the need for clinical trials demonstrating cardiovascular risk reduction with lipoprotein(a)-lowering therapies.

Main Methods:

  • Review of existing literature on lipoprotein(a) and its association with cardiovascular disease.
  • Analysis of data from clinical trials involving antisense oligonucleotides targeting apolipoprotein B and apolipoprotein(a).
  • Evaluation of the impact of therapies like niacin, PCSK9 inhibitors, CETP inhibitors, mipomersen, and AKCEA-APO(a)-LRx on lipoprotein(a) levels.

Main Results:

  • Antisense oligonucleotides, mipomersen and AKCEA-APO(a)-LRx, effectively reduce lipoprotein(a) levels.
  • Mipomersen lowered lipoprotein(a) by 20-50%, while AKCEA-APO(a)-LRx achieved 50-80% reduction in phase 2 studies.
  • Despite significant reductions in lipoprotein(a), no randomized controlled trial has yet proven that lowering lipoprotein(a) reduces cardiovascular disease risk.

Conclusions:

  • Antisense oligonucleotides represent a promising therapeutic strategy for managing elevated lipoprotein(a).
  • Further research, including large-scale phase 3 trials, is crucial to establish the cardiovascular benefits of these novel treatments.
  • The anticipated phase 3 study of AKCEA-APO(a)-LRx is critical for determining its role in reducing cardiovascular disease outcomes.