Epilepsy drug may offer hope for ALS treatment, Harvard stem cell researchers report

Today’s blog is the third in as many days about amyotrophic lateral sclerosis (ALS) research and this one may be the most tantalizing. Earlier this morning, the Harvard Stem Cell Institute (HSCI) announced the publication of two reports that point to an already approved epilepsy drug as a possible treatment for ALS, also known as Lou Gehrig’s disease.

As I mentioned in yesterday’s blog , ALS is a dreadful disease you wouldn’t wish on your worst enemy. It is usually fatal within 4-5 years of initial diagnosis. The disease occurs when the cells in the brain or spinal cord that send signals to the muscle to move, called motor neurons, die off. The eventual cause of death is often the inability to breathe when the muscles of the diaphragm fail.

Today’s studies in Cell Stem Cell and Cell Reports , led by HSCI principal faculty member Kevin Eggan, rely on the induced pluripotent stem cell (iPSC) technique pioneered by Nobel Winner Shinya Yamakana . Eggan’s team used skin samples from people with ALS as well as people without the disease to generate patient specific neurons. Despite the fact that hundreds of mutations exist that cause ALS, the team surprisingly found a consistent pattern in the iPSC-derived cells: the neurons from people with ALS sent out random, overly excited signals compared to the healthy neurons, which needed specific stimulation to set off activity.

In collaboration with colleague Clifford Woolf, who co-directs HSCI’s Nervous System Disease Program, the research team identified a vicious biological cycle in which the overly excited activity of the ALS neurons led to abnormally folded proteins in the neurons, which in turn increased the neurons’ hyperactivity. In a Harvard press release , Woolf commented on the implications of these results:

The convergence on a single mechanism offered a very attractive place to intervene therapeutically. It looked like there’s a deficit in potassium channels in the ALS motor neurons, and that led us to then test whether drugs that open the potassium channels may reduce this hyperexcitability. And indeed that’s exactly what we found. We found that retigabine, which has recently been approved as an anticonvulsive, normalized this activity.

The next step? Carry out a clinical trial that first tests the safety of the drug in ALS patients. As Eggan cautions:

The whole intact nervous system is more complicated than the cells that we have in the dish at the moment, and now the next step is to say whether or not the drug will be helpful in that context, and it’s too early to say for sure.

Still, these exciting studies show the game-changing power of iPSC technology to help scientists understand complex disease and to identify potential treatments. In this regard Dr. Woolf reflected about the big picture:

I think it’s the beginning of a complete change in the way we do medicine for serious diseases like this. In a traditional clinical trial, you give the patient the placebo or an active ingredient to see the effects they have, and it’s over. Here we can take the same stem cell lines and have an infinite capacity to do clinical trials in a dish.

For information about CIRM-funded ALS stem cell research, visit our ALS fact sheet.

Todd Dubnicoff