Familial Hypercholesterolemia: JACC Focus Seminar 4/4

Area of Science:

• Cardiovascular Medicine
• Genetics
• Pharmacology

Background:

• Familial hypercholesterolemia (FH) requires early detection and LDL cholesterol normalization for cardiovascular disease (CVD) prevention.
• Effective management involves combining lipid-lowering therapies that target complementary metabolic pathways, even in severe cases.

Purpose of the Study:

• To review current and emerging therapeutic strategies for managing familial hypercholesterolemia.
• To highlight advancements in targeting both LDL receptor-dependent and independent pathways for cholesterol reduction.

Main Methods:

• Discussion of LDL receptor-dependent treatments targeting PCSK9 via protein inhibition, mRNA inhibition (ASO, siRNA), and gene editing.
• Review of LDL receptor-independent treatments targeting ANGPTL3 with monoclonal antibodies or ASO/siRNA.
• Mention of ongoing gene therapy trials for homozygous FH (HoFH) using adenovirus vectors and CRISPR-Cas technology.

Main Results:

• PCSK9 remains a primary target for adjunctive therapy to statins and ezetimibe.
• Novel LDL receptor-independent therapies targeting ANGPTL3 are available or in development.
• Gene therapy and CRISPR-Cas technology show promise for potential one-time curative treatments for FH.

Conclusions:

• A combination of lipid-lowering therapies can effectively manage FH, including severe phenotypes.
• Emerging genetic and molecular therapies offer new avenues for treating FH, potentially leading to curative options.