Recent progress in gene therapy for familial hypercholesterolemia treatment

Figures

• 

  Figure 1. The working mechanism of first-line drug statins, PCSK9 inhibitors, and ezetimibe Statins inhibit HMG-CoA reductase, thereby reducing cholesterol biosynthesis and lowering plasma cholesterol levels. Ezetimibe inhibits the absorption of dietary cholesterol by NPC1L1 in the intestine. PCSK9 inhibitors improve the stability of LDLR, thereby enhancing the LDLR-mediated clearance of cholesterol from blood.

• 

  Figure 2. The pros and cons of the CRISPR/Cas9-derived nuclease, base editor, and prime editor systems

• 

  Figure 3. ANGPTL3 as gene therapy targets ANGPTL3 inhibits the activities of LPL and EL, which hydrolyze TGs and phospholipids respectively within VLDLs. Reduction in ANGPTL3 expression enhances LPL and EL activity, thereby increasing the conversion of VLDL into VLDL remnants with accelerated clearance and reducing VLDL conversion into LDL. As elevated LDL levels in blood vessels contribute to atherosclerosis, targeting ANGPTL3 expression through gene editing (e.g., BE or CRISPR/Cas9) or gene inactivation tools (siRNA or ASO) can potentially reduce the risk of ASCVD.

• 

  Figure 4. ASGR1 as gene therapy targets ASGR1-mediated endocytosis and lysosomal degradation of serum glycoproteins lead to the mTORC1 pathway activation, AMPK pathway inhibition, as well as the translocation of transcription factor SREBPs from the ER to the nucleus, thereby leading to the upregulation of genes involved in cholesterol biosynthesis and PCSK9-mediated LDLR degradation. Importantly, ASGR1 also acts through the AMPK pathway to downregulate LXRα, which in turn downregulates ABC-family transporters ABCG5/G8 to inhibit cholesterol efflux into bile and intestine. In theory, ASGR1 knockout (ASGR1 KO) would inhibit intracellular cholesterol synthesis, promote ABCG5/G8-mediated cholesterol efflux, and promote LDLR recycling to enhance the LDLR-mediated clearance of blood cholesterol (dotted lines).