Emerging lipid-lowering therapies targeting PCSK9 and ANGPTL3, alongside future gene-editing technologies, offer promising approaches for managing familial hypercholesterolemia.
Emerging therapies targeting PCSK9, ANGPTL3, and gene editing (CRISPR) offer promising synergistic approaches to normalize LDL cholesterol in patients with familial hypercholesterolemia.
Detecting familial hypercholesterolemia (FH) early and "normalizing" low-density lipoprotein (LDL) cholesterol values are the 2 pillars for effective cardiovascular disease prevention in FH. Combining lipid-lowering therapies targeting synergistic/complementary metabolic pathways makes this feasible, even among severe phenotypes. For LDL receptor-dependent treatments, PCSK9 remains the main target for adjunctive therapy to statins and ezetimibe through a variety of approaches. These include protein inhibition (adnectins), inhibition of translation at mRNA level (antisense oligonucleotides or small interfering RNA), and creation of loss-of-function mutations through base-pair editing. For patients with little LDL receptor function, LDL receptor-independent treatment targeting ANGPTL3 through monoclonal therapies are now available, or in the future, antisense/small interfering RNA-based approaches offer alternative approaches. Finally, first-in-human studies are ongoing, testing adenovirus-mediated gene therapy transducing healthy LDLR DNA in patients with HoFH. Further development of the CRISPR cas technology, which has shown promising results in vivo on introducing PCSK9 loss-of-function mutations, will move a single-dose, curative treatment for FH closer.
Brandts et al. (Mon,) conducted a review in Familial hypercholesterolemia. Lipid-lowering therapies was evaluated. Emerging lipid-lowering therapies targeting PCSK9 and ANGPTL3, alongside future gene-editing technologies, offer promising approaches for managing familial hypercholesterolemia.