Action Potential

Multiple sclerosis (MS) is a heterogeneous disease that affects primarily young adults and often leads to serious disability. We don't know what causes it, and we cannot cure it. This summer, in our July issue, we editorialized about the tragic crash-and-burn of the promising MS drug natalizumab (marketed as Tysabri(R)). In a nutshell - after passing preliminary clinical trials with flying colors, and being approved by the FDA in an accelerated procedure, natalizumab had to be pulled after just three months because a few patients came down with PML, a devastating, crippling or deadly, infection of brain oligodendrocytes. PML is caused by the JC virus, which most of us get exposed to at some point, without it ever doing any noticable harm. How exactly natalizumab would activate the somnolent JCV is unknown, in large part because we don't know enough about its life cycle and physiology. PML is extremely rare, and mice can't catch it - two facts that unfortunately tend to discourage research.

In response to our editorial, Richard Ransohoff from the Cleveland Clinic wrote us a letter putting forward an interesting hypothesis about the natalizumab - PML link. We had his letter peer-reviewed, and we published it in our October issue. Here's a summary of the idea:

Natalizumab works by interfering with a specific adhesion molecule that the myelin-attacking T cells in MS need to migrate into the brain. The same molecule also functions in cell adhesion in the bone marrow, where blood and immune cells are generated. It is known that natalizumab, as a side effect, leads to release of immature blood cells into the circulation. It has also been suggested that the specific genetic rearrangement that activates dormant JCV occurs in the bone marrow. Therefore natalizumab could lead to release of large numbers of JCV-infected immature cells in JCV carriers, overwhelming the immunosurveillance mechanisms that usually keep JCV in check.

Although we know that about 80% of the population have been exposed to JCV and carry antibodies to it, it is completely unknown how many carry dormant virus that could be activated. And there is no easy reliable test to find out.

Ransohoff's letter has triggered a small flurry of follow-up letters, with authors suggesting their own ideas, or variants on the Ransohoff hypothesis. Now, we can't really publish everyone's favorite thoughts on the subject in the printed pages of the journal - first, not all of them are as original as Ransohoff's, and second - it would never end! The journal is really meant for hard data; we publish hypotheses very, very rarely.

But this discussion itself is very much worth having. If there's any chance at salvaging natalizumab - apparently the most effective treatment for MS that's ever been available - and the entire class of drugs it represents, it will emerge from frank discussion among the experts. So why not have the discussion here, on our blog, on "Action Potential"? We'd be proud and happy to host your "virtual meeting".