Stem Cell Screen Identifies Target in ALS

Using a stem-cell-based screening method, a team of researchers based at institutions in Massachusetts and Connecticut identified a small molecule called kenpaullone as a potential therapy for amyotrophic lateral sclerosis (ALS).

Further studies revealed that the molecule appears to work by inhibiting the activity of two proteins, GSK3 and HGK. This data suggests the proteins may be potential targets at which to aim therapies in ALS.

Lee Rubin at the Harvard Stem Cell Institute in Cambridge, Mass., and colleagues note that their studies were made possible by recent scientific advances that allow researchers to generate large numbers of motor neurons from stem cells. Their findings demonstrate how this "disease in a dish" model makes it possible for scientists to:

  • identify potential therapies; and
  • test promising drug candidates on human ALS-affected cells before further developing them or advancing them to testing in human clinical trials.

The team published its findings online April 18, 2013 in Cell Stem Cell. To read the full report, for free, see: A Small Molecule Screen in Stem-Cell-Derived Motor Neurons Identifies a Kinase Inhibitor as a Candidate Therapeutic for ALS.

Kenpaullone promoted mouse motor neuron survival

The investigators screened approximately 5,000 small-molecule compounds in motor neuron cell cultures that were derived using embryonic stem cells from healthy mice or from mice with a disease resembling ALS caused by a mutation in the SOD1 gene.

When trophic (nourishing) factors were removed — a standard method of inducing cell death — the researchers found that a number of compounds promoted the health and survival of one or both motor neuron cell types. Of these, the most effective was kenpaullone.

In further studies conducted in the mouse motor neurons, the researchers confirmed that kenpaullone appeared to work by inhibiting the activity of the GSK3 and HGK proteins, and possibly via other as-yet-unidentified pathways. The data confirm the GSK3 and HGK proteins as possible targets for ALS therapies.

Kenpaullone increased survival of human motor neurons in disease-in-a-dish 'trial'

In order to determine whether their initial studies might apply to human ALS, the investigators generated motor neurons from a human embryonic stem cell line. When trophic factors were removed, treatment with kenpaullone prevented these cells from dying.

Lastly, in a disease-in-a-dish "trial" the team compared the effects of kenpaullone to those of two compounds — dexpramipexole and olesoxime — that failed in human ALS clinical trials.

  • Motor neurons were generated from induced pluripotent stem cells (iPSCs) taken from one unaffected (control) individual, one person with SOD1 ALS, and one person with ALS caused by a mutation in the TDP43 gene.
  • In all human cell cultures, treatment with kenpaullone increased motor neuron survival, while treatment with dexpramipexole had no effect, and treatment with olesoxime was associated with a smaller effect on survival that varied among the different motor neuron lines.

The researchers note that development of kenpaullone as a therapy for ALS likely would require chemical modification to improve its potency and ability to penetrate the central nervous system.

They say that different versions of their disease-in-a-dish trial, in which compounds can be tested on diseased human cells such as motor neurons, "will be extremely useful in choosing the best compounds to take into clinical studies and in selecting patients most likely to respond to particular treatments."

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