Long Noncoding RNA Facilitated Gene Therapy Reduces Atherosclerosis in a Murine Model of Familial Hypercholesterolemia

• atherosclerosis
• cholesterol
• genetic therapy
• RNA, long noncoding

Familial hypercholesterolemia (FH) is an autosomal-dominant disorder characterized by severe elevations in low-density lipoprotein cholesterol (LDL-C) levels and a 20-fold increased risk of premature cardiovascular disease. Although multiple causative genes have been identified, most FH cases are because of mutations in the LDLR, proprotein convertase subtilisin/kexin type 9, or apolipoprotein B genes.¹ Recent studies suggest that many patients with FH fail to achieve optimal LDL-C reduction despite high-intensity statin use and the recent addition of proprotein convertase subtilisin/kexin type 9 inhibitors.¹ Adeno-associated virus (AAV)-based gene therapy is currently approved or in clinical trials for >80 human diseases, and to address the substantial gap in treatment for patients with severe FH, hepatic AAV-LDL receptor-based gene therapy is currently in phase II clinical trials.

Long noncoding (lnc) RNAs form the vast majority of transcriptionally active regions and are arbitrary defined as transcripts >200 bps that biochemically resemble mRNA and yet do not template protein.² Although multiple lines of evidence implicate lncRNAs in a range of developmental processes and diseases, few lncRNA knockout studies have yielded robust phenotypes or demonstrated that proposed mechanisms are operational in vivo. Furthermore, lncRNA regulatory circuits have not been well explored for their potential therapeutic utility.

We recently showed that the lncRNA liver-expressed liver X receptor-induced sequence (LeXis) orchestrates cross-talk between the liver X receptor and sterol regulatory element-binding protein transcription factors to maintain hepatic sterol content …