Established and Emerging Nucleic Acid Therapies for Familial Hypercholesterolemia

Abstract

Familial hypercholesterolemia (FH) is a genetic disease that leads to elevated low-density lipoprotein cholesterol levels and risk of coronary heart disease. Current therapeutic options for FH remain relatively limited and only partially effective in both lowering low-density lipoprotein cholesterol and modifying coronary heart disease risk. The unique characteristics of nucleic acid therapies to target the underlying cause of the disease can offer solutions unachievable with conventional medications. DNA- and RNA-based therapeutics have the potential to transform the care of patients with FH. Recent advances are overcoming obstacles to clinical translation of nucleic acid-based medications, including greater stability of the formulations as well as site-specific delivery, making gene-based therapy for FH an alternative approach for treatment of FH.

Keywords: antisense oligonucleotide; coronary heart disease; familial hypercholesterolemia; low-density lipoprotein cholesterol; messenger RNA; nucleic acid therapies; proprotein convertase subtilisin/kexin type 9; small interfering RNA.

Figure 1:

Mechanism of action of antisense oligonucleotide (ASO) medications. In this case, an ASO drug (mipomersen) targets the mRNA encoding apolipoprotein B (apoB) in the nucleus. Apo B is the primary protein component of LDL-cholesterol. When the ASO binds to the mRNA encoding apoB, it triggers RNase H degradation of the apo B mRNA. Thus, apo B mRNA is not translated into protein, thereby reducing LDL cholesterol levels.

Figure 2:

Mechanism of action of an siRNA drug. In this case, an siRNA against PCSK9 is selectively taken up by hepatocytes after administration. The siRNA is then slowly released into the cytoplasm from endosome and loaded into the RNA-induced silencing complex (RISC). The RISC complex consists of Ago-2 (Argonaute-2), Dicer, and TRBP (transactivation response element RNA-binding protein) proteins. The siRNA unwinds, the sense strand is removed, and the antisense strand guides the RISC complex to the PCSK9 mRNA. The antisense strand then binds to the PCSK9 mRNA and then the Ago-2 in the RISC complex degrades the PCSK9 mRNA in the cytoplasm. One siRNA-RISC complex can target multiple mRNAs.

Figure 3:

Clinically relevant approaches for therapeutic delivery of nucleic acids in FH (created with BioRender^®).