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RNA-targeted therapeutics for lipid disorders

Tsimikas, Sotirios

doi: 10.1097/MOL.0000000000000549
THERAPY AND CLINICAL TRIALS: Edited by Erik S.G. Stroes and Gerald F. Watts

Purpose of review To summarize recent developments in the field of RNA-directed therapeutics targeting lipid disorders that are not effectively managed.

Recent findings Despite a number of approved therapies for lipid disorders, significant unmet needs are present in treating persistently elevated LDL-cholesterol, remnant-cholesterol, triglycerides and lipoprotein(a) [Lp(a)]. Small molecules and antibodies are effective modalities, but they are unable to adequately treat many patients with abnormal lipid parameters. Targeting mRNA with oligonucleotides to prevent protein translation is a relatively novel method to reduce circulating atherogenic lipoproteins. Small inhibiting RNA (siRNA) molecules targeting proprotein convertase subtilisin kexin type 9 to reduce LDL-C, and antisense oligonucleotides (ASO) targeting apolipoprotein C-III (apoC-III) to reduce triglycerides, angiopoietin-like 3 (ANGPTL3) to reduce LDL-C and triglycerides and apolipoprotein(a) (LPA) to reduce Lp(a) are currently in or just completed phase 1–3 trials. Fundamental differences exist in chemistry, delivery and mechanism of action of siRNA and ASOs.

Summary Novel RNA therapeutics are poised to provide highly potent, specific and effective therapies to reduce atherogenic lipoproteins. As these compounds are approved, clinicians will be able to choose from a broad armamentarium to treat nearly all patients to acceptable goals in order to reduce risk of cardiovascular disease and events.

Vascular Medicine Program, Sulpizio Cardiovascular Center, Division of Cardiovascular diseases, University of California San Diego School of Medicine, California, USA

Correspondence to Sotirios Tsimikas, MD, FACC, Vascular Medicine Program, Sulpizio Cardiovascular Center, Division of Cardiovascular diseases, University of California San Diego School of Medicine, 9500 Gilman Drive, BSB 1080, La Jolla, CA 92093-0682, USA. E-mail: stsimikas@ucsd.edu

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