👤 Sylvia Stankov

Plasma triglycerides (TGs) are causally associated with coronary artery disease and acute pancreatitis. Apolipoprotein A-V (apoA-V, gene We used hydrogen-deuterium exchange mass spectrometry to determine the secondary structure of human apoA-V in lipid-free and lipid-associated conditions and identified a C-terminal hydrophobic face. Then, we used genomic data in the Penn Medicine Biobank to identify a rare variant, Q252X, predicted to specifically eliminate this region. We interrogated the function of apoA-V Q252X using recombinant protein Human apoA-V Q252X carriers exhibited elevated plasma TG levels consistent with loss of function. Deletion of apoA-V's C-terminus leads to reduced apoA-V bioavailability Show less

Effective lipid lowering therapies are essential for the prevention of atherosclerosis and cardiovascular disease. Available treatments have evolved in both their efficacy and their frequency of administration, and currently include monoclonal antibodies, antisense oligonucleotides and siRNA approaches. However, an unmet need remains for more effective and long-lasting therapeutics. Gene editing permanently alters endogenous gene expression and has the potential to revolutionize disease treatment. Despite the existence of several gene editing approaches, the CRISPR/Cas9 system has emerged as the preferred technology because of its high efficiency and relative simplicity. This review provides a general overview of this promising technology and an update on the progress made towards the development of treatments of dyslipidemia. The recently started phase 1b gene editing clinical trial targeting PCSK9 in patients with heterozygous familial hypercholesterolemia and cardiovascular disease highlights how gene editing may become available to treat not only patients affected by rare disorders of lipid metabolism, but also patients that are difficult-to-treat or at high risk. Other targets like ANGPTL3, LDLR, and APOC3 are on track for further pre-clinical development. The identification of novel targets using electronic health record-linked biobanks and human sequencing studies will continue to expand the potential target pool, and clinical assessment of treated patients will provide essential efficacy and safety information on current strategies. Gene editing of genes regulating lipid metabolism holds promise as an exciting new therapeutic approach. However, since gene editing permanently alters a patient's genome, its therapeutic application in humans will require careful safety assessment and ethical considerations. Show less