Emerging Therapies For FH Reviewed in JACC Focus Seminar

Earlier diagnosis of familial hypercholesterolemia (FH) as well as new and emerging lipid-lowering therapies may achieve the goal of reducing lifetime cholesterol exposure and reduce the risk of events from atherosclerotic cardiovascular disease (ASCVD), according to a Focus Seminar published Oct. 25 in the Journal of the American College of Cardiology.

Julia Brandts, MD, and Kausik K. Ray, MD, FACC, provide a review of FH, including heterozygous FH (HeFH), the most common form, and homozygous FH (HoFH), along with their diagnosis and goals of treatment.

They explain that combination lipid-lowering therapies targeting synergistic and complementary metabolic pathways make it possible to "normalize" LDL-C, even among persons with more severe phenotypes, especially with earlier diagnosis. They note that later diagnosis, for example after a premature ASCVD event in HeFH, typically requires more intensive therapy to overcome the missed years of cumulative exposure to therapy.

Initial therapy for FH consists of statins, in combination with ezetimibe and monoclonal antibodies against PCSK9. The authors review the findings and mechanisms for novel LDL-receptor-dependent treatments that target PCSK9 through a variety of approaches including 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, as well as LDL-receptor-independent treatment targeting ANGPTL3 through monoclonal therapies, which are now available, or potentially in the future with antisense/small interfering RNA-based approaches.

Also reviewed are ongoing first-in-human studies assessing an adenovirus-mediated gene therapy transducing healthy LDL-receptor DNA in patients with HoFH and the early development of CRISPR-Cas therapy, which may one day offer a single-dose, curative treatment for FH.

Detecting FH early and "normalizing" LDL-C values are the two pillars for effective cardiovascular disease prevention in FH, write the authors. They emphasize that to affect FH care at a global level, earlier diagnosis is as important as the implementation and affordability of new and emerging therapies.

Clinical Topics: Cardiovascular Care Team, Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: Hydroxymethylglutaryl-CoA Reductase Inhibitors, PCSK9 protein, human, Proprotein Convertase 9, Cholesterol, LDL, RNA, Small Interfering, Hyperlipoproteinemia Type II, Ezetimibe, Oligonucleotides, Antisense, Adenoviridae, Antibodies, Monoclonal, Clustered Regularly Interspaced Short Palindromic Repeats, Base Pairing, RNA, Messenger, Cardiovascular Diseases, Centers for Medicare and Medicaid Services, U.S., Loss of Function Mutation, Receptors, LDL, Cardiology, Metabolic Networks and Pathways, Phenotype, Genetic Therapy, DNA

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