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Updated: Jan 24, 2026
Intrathecal Delivery of Antisense Oligonucleotides in the Rat Central Nervous System
Published on: October 29, 2019
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.
Insights
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.
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.
Purpose Of Review:
High 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 date, no randomized controlled trial has demonstrated that lowering of lipoprotein(a) leads to lower risk of cardiovascular disease.
Recent Findings:
Synthetic oligonucleotides can be used to inactivate genes involved in disease processes. To lower lipoprotein(a), two antisense oligonucleotides have been developed, one targeting apolipoprotein B and one targeting apolipoprotein(a). Mipomersen is an antisense oligonucleotide targeting apolipoprotein B and thereby reducing levels of all apolipoprotein B containing lipoproteins in the circulation. Mipomersen has been shown to lower lipoprotein(a) by 20-50% in phase 3 studies. AKCEA-APO(a)-LRx is the most recent antisense oligonucleotide targeting apolipoprotein(a) and thereby uniquely targeting lipoprotein(a). It has been tested in a phase 2 study and has shown to lower lipoprotein(a) levels by 50-80%. The treatment of elevated lipoprotein(a) levels with the newest antisense oligonucleotides seems promising; however, no improvement in cardiovascular disease risk has yet been shown. However, a phase 3 study of AKCEA-APO(a)-LRx is being planned with cardiovascular disease as outcome, and results are awaited with great anticipation.
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