Demystifying HDL Cholesterol-A "Human Knockout" to the Rescue?

Abstract

The substantial cost associated with failure of a therapeutic approach in a large outcomes-based clinical trial, as has occurred recently for multiple compounds targeting HDL cholesterol metabolism, has led to intense interest in improved target selection. Careful study of humans who carry mutations that inactivate a putative drug target leverages naturally occurring genetic variation to study the impact of lifelong deficiency of a specific protein. As such, human genetics research can provide an opportunity to confirm the physiologic relevance of a target in humans before large-scale investments in drug development. Naturally occurring human DNA sequence variation can provide the foundation for important insights into disease biology and novel therapeutic strategies. Within the field of lipid metabolism, the rapid clinical development of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors to reduce LDL cholesterol provides proof-of-concept for the potential of this approach. Following the initial 2003 discovery of a gain-of-function mutation in the gene PCSK9 (proprotein convertase subtilisin/kexin type 9)3 associated with significantly increased LDL cholesterol, a 2005 report noted that about 2% of black individuals harbor an inactivating (premature stop) mutation in the PCSK9 gene. Carriers of this mutation benefitted from lifelong lower LDL cholesterol concentrations and inborn protection from coronary disease without detectable toxicity (1). Further, the identification of healthy individuals with 2 inactivating mutations, effectively “human knockouts” for PCSK9, further increased optimism that the protein could be targeted without off-target effects. These observations provided additional support for the hypothesis that pharmacologic inhibition of PCSK9 might similarly lower LDL cholesterol and decrease vascular risk. Translational research studies demonstrated that PCSK9 plays a previously unrecognized role in preventing hepatic uptake of LDL cholesterol by accelerating the catabolism of LDL receptors. These findings led to a pharmaceutical arms race to develop PCSK9 inhibitors using monoclonal antibody or RNA interference approaches. …