My new favorite drug?

I’ve written here before that the cholesterol-lowering medications, the statins, have positive effects on a variety of brain diseases and injuries in a variety of animal models (Alzheimer’s, Parkinson’s, stroke), with relatively few side effects. The thought is that they do this by lowering cholesterol, and cholesterol is quite relevant not only for hypertension and cardiac disease, but also for Alzheimer’s disease, for instance. Statins also have anti-inflammatory effects [see my post of Jan 28], which could be due to lowering cholesterol, and possibly by other pathways. Nonetheless, it is said that some 20% of patients cannot tolerate statin side effects, which brings me to the topic of this post. A new protein (PCSK9)(quite a mellifluous name) has recently been found to naturally lower LDL-cholesterol, apparently its normal function. Amazingly, rare individuals with mutations in the gene for PCSK9, which completely disable it, have extremely low LDL-cholesterol levels. Moreover, the people have an 88% lower risk of developing heart disease compared to normal folks. (Recall that cardiovascular disease is the number 1 cause of death worldwide) Equally encouraging is the finding that the rare folks with complete absence of PCSK9 appear to be very healthy – meaning that drugs that block PCSK9 are predicted to have no side effects! Many pharmaceutical companies have jumped on this lead and Regeneron and Amgen have each tested antibodies directed against PCSK9 in phase II clinical trials, and report very effective lowering of LDL-cholesterol levels. Large phase III trials have already begun.

What I’d like to see now are tests of such PCSK9 antibodies in mouse models of brain disorders where inflammation is involved. What I have found so far is that blocking PCSK9 in cell culture reduces the death of several types of neurons. On the other hand, knocking down PCSK9 levels in zebrafish embryos leads to their death, which does not happen in the humans without the normal PCSK9 gene, of course. In addition, there is a bit of evidence that blocking PCSK9 protects against inflammation in macrophages, which is very encouraging also.

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