Nucleic acid-based therapies, including RNA-targeting and gene-editing approaches, offer a promising paradigm shift for durable and precision management of severe or refractory dyslipidemias.
Genetic determinants play a central role in the development of dyslipidemias, which are major contributors to atherosclerotic cardiovascular disease (ASCVD), aortic valve disease, and acute pancreatitis. With conventional lipid-lowering therapies, such as statins, many patients with genetic dyslipidemias remain inadequately controlled while other patients are unable to tolerate them, necessitating ongoing research and development of innovative therapies. Several therapeutic lipid targets-including proprotein convertase subtilisin/kexin type 9 (PCSK9), lipoprotein(a) Lp(a), apolipoprotein (apo) C-III (APOC3), and angiopoietin-like protein 3 (ANGPTL3)-have been identified and validated through human genetic and epidemiologic studies. Emerging ribonucleic acid (RNA) targeting and gene-editing therapies now offer the potential for durable correction of these metabolic disturbances. Small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) targeting PCSK9, Lp(a), apo C-III and ANGPTL3 have shown marked efficacy in lowering atherogenic lipoproteins and triglycerides, while DNA base-editing approaches including clustered regularly interspaced short palindromic repeats (CRISPR), CRISPR associated protein 9 (Cas9) and related base-editing techniques, aim to provide long-term or even permanent gene silencing to control atherogenic lipids. Together, these innovations mark a paradigm shift toward precision, gene-based lipid management, expanding therapeutic options, improving clinical outcomes, and addressing unmet medical needs in patients with severe or refractory dyslipidemias or in those unable to tolerate standard therapies.
Robert A. Hegele (Thu,) studied this question.
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