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Published on: November 17, 2018
Gene silencing approaches for the management of dyslipidaemia
Giuseppe Danilo Norata1, Gianpaolo Tibolla, Alberico Luigi Catapano
1Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133, Milan, Italy. danilo.norata@unimi.it
Abstract:
The key role of dyslipidaemias in determining cardiovascular risk has been well established, and statins often provide effective therapeutic management. However, many patients do not achieve recommended lipid levels despite maximal therapy, and some cannot tolerate high-dose statin therapy. Recently, genetic insights into mechanisms underlying regulation of lipoprotein metabolism have expanded the potential targets of drug therapy and led to the development of novel agents, including development of gene silencing approaches. These therapeutic options include the modulation of synthesis in the liver, maturation in the circulation, and catabolism of lipoproteins. In this review, we discuss the pharmacological consequences of silencing apolipoprotein B, apolipoprotein (a), microRNA 33, proprotein convertase subtilisin/kexin type 9, and apolipoprotein C-III. New potential targets such as other microRNAs, diacylglycerol acyl transferase-1, and angiopoietin-like protein 3 are also presented. The pharmacological consequences of gene silencing and the advancement of these therapeutic approaches in clinical development will be examined.
Insights
Gene silencing offers new ways to manage dyslipidemias when statins fail. Novel agents target lipoprotein metabolism, expanding cardiovascular risk reduction options.
Area of Science:
- Lipid metabolism and cardiovascular disease genetics.
- Pharmacological interventions for dyslipidemia.
Background:
- Dyslipidemias significantly increase cardiovascular risk.
- Statins are effective but not sufficient for all patients.
- Genetic insights reveal new therapeutic targets for lipoprotein disorders.
Purpose of the Study:
- To review novel gene silencing therapies for dyslipidemia.
- To discuss pharmacological consequences of targeting specific genes and microRNAs.
- To examine emerging targets in lipoprotein metabolism.
Main Methods:
- Review of current literature on gene silencing approaches.
- Analysis of pharmacological effects of targeting apolipoprotein B, apolipoprotein (a), microRNA 33, PCSK9, and apolipoprotein C-III.
- Discussion of novel targets like DGAT-1 and ANGPTL3.
Main Results:
- Gene silencing modulates lipoprotein synthesis, maturation, and catabolism.
- Specific gene targets show promise in managing lipid levels.
- Several novel agents are advancing in clinical development.
Conclusions:
- Gene silencing represents a promising therapeutic strategy for dyslipidemia.
- These approaches offer alternatives for patients unresponsive or intolerant to statins.
- Further clinical development is crucial for these novel therapies.
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