Mutations are bad, right?
Not always. Some DNA changes are completely neutral. That’s how the human genome came to have so many variations. And some mutations are actually advantageous.
A case in point is the PCSK9 gene. So-called “loss-of-function” mutations that prevent the protein encoded by this gene from functioning properly actually lead to lower cholesterol levels.
Researchers at several pharmaceutical companies have taken inspiration from these PCSK9 mutations. They are now developing drugs that would block its function in people with non-mutated forms of the gene. These drugs, though still in the early stages of testing, may offer a new way for the tens of millions of Americans with high cholesterol to get their levels under control.
The PCSK9 protein binds to LDL cholesterol receptors on the surface of cells. Once cholesterol binds to the receptor too, the whole complex is internalized into the cell, and the receptor is degraded. When PCSK9 function is missing, the LDL receptor is able to recycle back to the cell’s surface after dropping off its cholesterol cargo in the cells, allowing it to sop up more “bad” cholesterol from the bloodstream. There doesn’t seem to be any downside to the cholesterol-lowering PCSK9 mutations, suggesting that targeting the protein with drugs could be safe and effective way of reducing cholesterol.
One company, Amgen, is tackling the problem with antibodies that attach to the PCSK9 protein outside of cells, targeting it for destruction by the immune system. Two others, Isis and Alnylam, are using small pieces of RNA designed to go inside cells and keep the PCSK9 protein from being made in the first place. All three companies have shown reductions of LDL cholesterol in early animal experiments. A review of their findings appeared recently in Nature Publishing Group’s Science-Business eXchange.
People who need to lower their cholesterol but can’t tolerate statins stand to benefit most from any PCSK9 inhibitors that are developed. But these drugs might be good for those taking statins too. High doses of statins can actually increase the amount of PCSK9 in the body. Taking a PCSK9 inhibitor along with a statin could help cut off this potentially backtracking side effect. Unfortunately, unlike statins, none of the PCSK9 inhibitors under development can be taken orally. They all need to be delivered through an injection.
Many years of clinical trials are ahead for each of these drugs. Researchers will need to assess both their safety and efficacy. But it’s exciting to see a genetics discovery be so quickly translated into an idea that could help millions of people.