October 4, 2018
View Full PaperRNA-targeted therapeutics for lipid disorders
Key Result
Novel RNA therapeutics, including siRNA and ASOs targeting PCSK9, apoC-III, ANGPTL3, and LPA, are poised to provide highly potent and specific therapies to reduce atherogenic lipoproteins.
Structured PICO
Do RNA-targeted therapeutics reduce atherogenic lipoproteins in patients with lipid disorders?
P
Population
Patients with lipid disorders not effectively managed (persistently elevated LDL-cholesterol, remnant-cholesterol, triglycerides and lipoprotein(a))
I
Intervention
RNA-targeted therapeutics (siRNA targeting PCSK9, ASO targeting apoC-III, ANGPTL3, and LPA)
O
Outcome
Reduction of circulating atherogenic lipoproteinssurrogate
RNA-targeted therapeutics offer a promising new approach to effectively lower atherogenic lipoproteins in patients with inadequately managed lipid disorders.
Abstract
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.