Given the potential of human pluripotent stem cells and their differentiated cell types to model keys aspects of neurological disease, an obvious extension of this platform is in its use for drug discovery and predictive toxicology. As iPS cells can be generated from different patient populations, a diversity of drug responses and toxicity profiles could potentially be captured. High rates of attrition of new drugs are mostly attributed

to failures in clinical efficacy or unforeseen toxicities and safety concerns, often occurring in later stages of clinical trials. Nearly 90% of new drugs tested in humans fail to ultimately come to clinical approval, with central nervous system disorders as a therapeutic area, among those with the highest rate of attrition (Kola and Landis, 2004). Arguably, these failures Cabozantinib purchase have resulted from a reliance on imperfect models used during preclinical development. One could envision using human pluripotent cell-based assays in lead optimization for efficacy and also to identify, prior to first-in-human studies, drug toxicities. As disease-specific stem cell models for neurological diseases continue to be validated, they are poised

to become unprecedented tools for drug discovery using human cells (Ebert and Svendsen, 2010 and Rubin, 2008). However, before their full potential can be realized, several challenges must be overcome. IWR-1 purchase It will be critical to identify robust assays that display disease-relevant phenotypes and are readily amenable to large-scale drug screening. For example, high-throughput screening of compounds that improve motor neuron survival in SMA and ALS is one such achievable goal (Di Giorgio

et al., 2008, Ebert et al., 2009 and Rubin, 2008). Thus, optimizing stem cell cultures and differentiation protocols for large-scale, automated, multiwell formats will be important technical goals. Pluripotent stem cells may also find an important function in predicting whether lead compounds identified using the cells of a single patient will be equally effective in a large cohort of individuals. To this end, one could imagine convening a large set of iPS cell lines, which could then be arrayed in not multiwell format. These “arrayed” stem cells would then be differentiated in parallel within the multiwell format into neurons that then could be exposed to the novel lead molecule. If the newly identified lead compounds worked well in disease models made from each of the genetically diverse cell lines within the array, then it could provide additional confidence that the compound in hand would function in a large number of patients. In turn if compounds are found to function in the neurons of some but not all stem cells within the array, the genetic signature of cells that respond best can be identified. This information would then be used to convene a clinical trial and administer the compound only to individuals with the response genotype.