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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

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November 14, 2002

Statins and Multiple Sclerosis

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Posted by Derek

I recently mentioned the non-cholesterol effects of HMG-CoA reductase inhibitors (statins,) so I thought I'd follow up on that with a discussion of the recent news (Nature, Nov. 7) that they could be beneficial for multiple sclerosis.

The mechanism of MS is clear, up to a point. (I know, everything is clear, up to a point, but bear with me.) It's an autoimmune disease, a T-cell response to the body's own myelin sheaths around the nerves. This inflammation damages the myelin (a full immune assault damages just about anything,) and thus affects nerve impulse transmission. Over time, the neurons themselves are irreversibly damaged (or so it seems; reversal of neurological damage is a hot topic these days, and no one's sure what might be possible eventually.) The course of the disease varies a great deal from person to person, since immune systems vary, too. Current therapy can slow the progression down a bit, but nothing stops it.

The idea that statins might help in something like MS isn't actually new. The drugs have long been known to have some immunological effects: as far back as 1995 — yep, way back then — a study showed that heart transplant patients had a better outcome when pretreated with pravastatin.) Since then, a number of miscellaneous signaling pathways involved in inflammation have been shown to be affected by one statin or another. (So many, in fact, that it was getting hard to sort out what was going on.)

The latest work is a very nice study using a mouse model of MS called EAE (experimental autoimmune encephalomyelitis.) It's a pretty decent surrogate for the disease, brought on by deliberate (and heavy) immunization with peptides that are close enough to myelin's surface composition to set off the autoimmune response. There are several recipes for doing that, some of which only work in specific strains of mice, which cause different types of impairment (more or less severe, chronic versus repeating, and so on.)

The statin used was atorvastatin (known to the world, and to nearby planets if Pfizer's marketing department has anything to do with it, as Lipitor.) I note without comment that one of the paper's authors was the recipient of an "Atorvastatin Research Award" from Pfizer, but their choice of this particular compound was justified. Two years ago, it was found to be more potent on immune targets in vitro.

Giving the drug before symptoms set in was effective at lessening them. In fact, the statin even helped after waiting until the peak of the illness, which is a pretty severe test. All this was confirmed on the tissue and molecular levels; the results look very solid indeed.

So how does it work? Probably not through cholesterol lowering per se. But the HMG-CoA reductase enzyme that the statins inhibit produces mevalonate, which is a molecule that does seem to have some effects on immune function. Outside of that whole pathway, statins seem to affect production (although it's not clear how) of a regulatory protein called CIITA. That one's involved in presenting antigens to helper T cells, a process very close to presenting a pack of bloodhounds with someone's dirty sock. So it could be that the T-cell attack on myelin is thrown off at the very beginning.

There are other mechanisms, not mutually exclusive. Statins have also been shown to affect a protein called LFA-1, which is known to be important for T-cell migration. Perhaps even if they're on the scent, they get diverted at the last minute by this pathway. (One way to check would be to use pravastain, which doesn't seem to affect LFA-1, interestingly.)

Unraveling all this is going to keep a of people up late in the lab for some time to come. For now, atorvastatin is going into human trials on MS patients. You can bet that as the mechanism comes more into focus that drug companies will be ready to screen their compound banks again, though. Statins are a very good start in this area, but they don't have to be the last word.

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