Genetic Targets

The PCSK9 gene plays a critical role in controlling blood LDL-C levels through regulation of the LDL receptor. Reducing PCSK9 protein in the blood improves the ability of the liver to clear LDL-C. 

PCSK9 has been validated as a target through both human genetics and human pharmacology studies. As reported in The New England Journal of Medicine, one study found that adults with naturally occurring loss-of-function mutations in the PCSK9 gene had LDL-C levels that were significantly lower than in adults without a mutation, and those with a mutation had an 88% lower risk of ASCVD. Human genetic studies have also shown that carrying naturally occurring loss-of-function mutations in one or both copies of the PCSK9 gene is not associated with serious adverse health consequences. 

In addition, there are approved treatments that target PCSK9 to lower LDL-C. PCSK9-lowering medicines have proven to be safe, effectively lower LDL cholesterol, and significantly reduce risk of heart attack and stroke. 
 

The ANGPTL3 gene regulates both cholesterol and triglycerides contributing to ASCVD risk, independent of the PCSK9 pathway. Targeting ANGPTL3 in the liver and disrupting protein production may lead to reductions in LDL-C and triglyceride levels.

ANGPTL3 has emerged as a validated therapeutic target to promote lowering of LDL-C, as shown in both human genetics studies and human pharmacology studies. Studies done in humans with naturally occurring loss-of-function mutations in the ANGPTL3 gene have shown extremely low levels of triglycerides and LDL-C. Subsequent studies have determined that there are no apparent adverse health consequences observed in patients who naturally lack ANGPTL3 function. 

Multiple therapeutic approaches targeting ANGPTL3 have been developed or are being evaluated in the clinic and provide further validation for ANGPTL3 as a target. A monoclonal antibody targeting ANGPTL3 has been approved for patients with homozygous familial hypercholesterolemia (HoFH) in the U.S. 

The LPA gene regulates lipoprotein(a), or Lp(a), which is a liver-derived lipoprotein that circulates in blood. It is very similar to an LDL particle, though it has another protein attached to it called apolipoprotein(a), or apo(a). High blood levels of Lp(a) contribute to risk of ASCVD, including ASCVD outcomes such as heart attack. 

Patients with high Lp(a) are distinct from those with high LDL-C – though both are at risk of ASCVD, there is a low correlation between blood LDL-C levels and blood Lp(a) levels. 

Both human genetics studies and human pharmacologic studies have validated the potential efficacy and safety of an Lp(a)-reducing medicine. DNA variants that cause increased circulating Lp(a) are among the strongest inherited drivers of risk for ASCVD as well as certain heart valvular diseases (e.g., aortic stenosis). By contrast, naturally occurring loss-of-function mutations in one or both copies of the LPA gene are associated with protection from these conditions and no apparent serious adverse health consequences.

In addition, recent human pharmacologic studies of investigational therapies targeting LPA expression in the liver have demonstrated the ability to potently lower circulating Lp(a) concentrations by greater than 80%. The potential for these medicines to lower the risk of recurrent ASCVD events in patients with high Lp(a) is being tested in ongoing cardiovascular outcomes trials. 

We believe that these prior studies provide substantial evidence for the potential utility of a single-course medicine to lower Lp(a) in a patient population with both high risk and high unmet need. In collaboration with Eli Lilly, we are working toward developing a novel gene editor to target the LPA gene through this research-stage program.