Translating Lipoprotein Genetics Into New Therapies

Human genetics has become the primary engine for identifying lipid-lowering drug targets and predicting therapeutic success or failure. Monogenic family studies and population-based sequencing identify individuals with lifelong loss-of-function variants in lipoprotein-regulatory genes who are simultaneously healthier and inadvertent proof-of-concept trial participants—the human knockout paradigm. This approach has driven approvals across multiple mechanistic classes targeting PCSK9 (proprotein convertase subtilisin/kexin type 9; low-density lipoprotein cholesterol lowering with demonstrated cardiovascular benefit), APOC3 (apolipoprotein C-III; olezarsen and plozasiran, both approved for triglyceride lowering in familial chylomicronemia syndrome), and ANGPTL3 (angiopoietin-like protein 3, evinacumab, approved for homozygous familial hypercholesterolemia), while Mendelian randomization prospectively identified HDL (high-density lipoprotein) cholesterol as a noncausal biomarker, predicting the failure of HDL-raising therapy in outcomes trials. RNA-based pharmacology— N -acetylgalactosamine-conjugated small interfering RNAs and antisense oligonucleotides—has emerged as a pragmatic platform for translating genetic target validation into durable, infrequently dosed therapies. Cardiovascular outcomes trials of these RNA-based agents are pending or have not yet been announced. Gene-editing approaches now extend this logic toward potentially permanent intervention. Genome-wide association studies and polygenic risk scores have expanded the landscape of candidate targets but have yet to achieve translational yield comparable to rare-variant genetics.