Research ArticleStem Cells

Drug Screening for ALS Using Patient-Specific Induced Pluripotent Stem Cells

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Science Translational Medicine  01 Aug 2012:
Vol. 4, Issue 145, pp. 145ra104
DOI: 10.1126/scitranslmed.3004052

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A Stepping Stone to ALS Drug Screening

Amyotrophic lateral sclerosis (ALS) is an untreatable disorder in which the motor neurons degenerate, resulting in paralysis and death. Induced pluripotent stem cell (iPSC) technology makes it possible to analyze motor neurons from patients with ALS and to use them for screening new candidate drugs. In new work, Egawa et al. obtained motor neurons by inducing differentiation of iPSC lines derived from several patients with familial ALS. These patients carried disease-causing mutations in the gene encoding Tar DNA binding protein-43 (TDP-43). The ALS motor neurons in culture recapitulated cellular and molecular abnormalities associated with ALS. For example, the authors found that mutant TDP-43 in the ALS motor neurons perturbed RNA metabolism and that the motor neurons were more vulnerable to cellular stressors such as arsenite. The researchers then used the ALS motor neurons in a drug screening assay and identified a compound called anacardic acid, a histone acetyltransferase inhibitor, that could reverse some of the ALS phenotypes observed in the motor neurons. The new work provides an encouraging step toward using motor neurons generated from iPSCs derived from ALS patients to learn more about what triggers the death of motor neurons in this disease and to identify new candidate drugs that may be able to slow or reverse the devastating loss of motor neurons.