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Stem Cells Identify Potential ALS Drug

Kelly Rae Chi

A stem cell assay shows that a new drug candidate for ALS might be more effective than two phase III failures. Could similar assays help predict drug failures as well? Read more...   

Because moving a drug candidate from the lab to the clinic costs hundreds of millions dollars, assays that better predict whether a compound will succeed in human trials could help pharmaceutical companies identify the most promising drugs in which to invest their resources.

A stem cell assay shows that a new drug candidate for ALS might be more effective than two phase III failures. Source: Cell Stem Cell

In a study published this week in Cell Stem Cell (1), researchers reported that a new stem cell-based assay actually pinpointed a potential small molecule treatment for amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease. In follow-up experiments, the treatment promoted cell survival better than two other drug candidates that had recently failed in phase III clinical trials.

“[The new strategy] could either be used in the late preclinical stage to confirm the cellular actions of particular leads, or even better as a driver of early exploratory preclinical testing, revealing new targets and pathways,” noted study coauthor Clifford Woolf, director of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital.

Researchers led by Lee Rubin at Harvard Medical School developed the new assay by taking embryonic stem cells from both healthy mice and those with a mutation in the gene SOD1 that is known to cause ALS in people. After differentiating the stem cells into motor neurons—the cells affected by ALS—the group exposed them to 5000 small molecule compounds, while also removing essential trophic factors from the cells’ environment in order to accelerate their death.

Among their hits, kenpaullone—an inhibitor of the enzyme GSK-3, which controls cell growth and death—stood out in their initial screen. It strongly promoted survival of both normal and mutated motor neurons and kept them morphologically healthy. In another experiment, the group showed that the drug decreased levels of SOD1, which is thought to aggregate in the motor neurons of people with the disorder.

Testing kenpaullone on motor neurons derived from induced pluripotent stem cells of two ALS patients with mutations in either SOD1 or TDP-43 (another protein associated with ALS), the team found that the small molecule substantially boosted MN survival—by 2- to 4-fold, depending on the dose—of both healthy and diseased cells, compared to untreated cells.

In contrast, two drug candidates that recently failed phase III clinical trials were less effective when tested in the same assay; dexpramipexole had no effect on patient-derived motor neurons, and olesoxime had a variable but moderately positive effect.

It’s not clear how the SOD1 mutation leads to the degeneration of motor neurons; knowing this biology could inform additional endpoints for the stem cell assay, said Alysson Muotri, assistant professor of pediatrics and cellular and molecular medicine at the University of California, San Diego, who was not involved in the new study.

What’s more, kenpaullone hasn’t been tested in living mice yet. And, as with all cell culture assays, it is an open question as to “the extent to which changes in neurons in a dish phenocopy complex diseases that may take many years to manifest, and if rescue of the phenotype by a hit in a screen will translate into therapeutic benefit in patients,” Woolf noted.

But Muotri sees great potential for stem cell-based assays and their use for drug discovery. “Stem cell based screens will definitely speed up drug discovery, bringing more powerful candidates to clinical trial,” said Muotri. “I can see this going into personalized medicine—we will be testing drugs and doses in motor neurons derived from each patient to personalize treatment.”


1. Yang, Y. M., S. K. Gupta, K. J. Kim, B. E. Powers, A. Cerqueira, B. J. Wainger, H. D. Ngo, K. A. Rosowski, P. A. Schein, C. A. Ackeifi, et al. 2013. A small molecule screen in Stem-Cell-derived motor neurons identifies a kinase inhibitor as a candidate therapeutic for ALS. Cell Stem Cell (April).