Translational genomics turns human genetic signals into therapies.

The PCSK9 story shows how genomics can shorten the bench-to-bedside path from variant discovery to first-in-class therapeutics. 

Gain-of-function mutations in PCSK9 raised LDL-C, while loss-of-function variants lowered LDL-C and ASCVD risk, pinpointing PCSK9-mediated LDLR degradation as a causal pathway.

These “experiments of nature” de-risked the target and guided the development of PCSK9 monoclonal antibodies (evolocumab, alirocumab) that restore LDLR by blocking PCSK9.