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- W1500527436 abstract "Abstract : Our objective was to screen libraries of several thousand compounds, including clinically approved drugs, for their ability to suppress the in vivo phenotypes observed in worm and fish models expressing mutant human TDP-43 related to ALS and validating hits in a mouse model. Our hypothesis was that chemical modifiers of TDP-43 in vivo function would provide new therapeutic approaches to ALS. Our screen of 3,750 FDA-approved compounds identified 20 active compounds, most of which were neuroleptics with the most potent being pimozide, as well as WithaferinA. In addition to the 4k FDA compounds, we screened 2k molecules that are structurally related to the neuroleptics as well as novel molecules. Also, we screened 4k novel derivatives of pimozide and identified several dozen active compounds. WithaferinA and pimozide were tested in TDP- 43 and SOD1 mice. Results suggest that the beneficial effect of Withaferin A in mutant SOD1 mice may be due in part to an upregulation of heat shock proteins (Hsp27 and Hsp70) and to reduction in levels of misfolded SOD1 species. Motor behaviors were not significantly improved or possibly worsened by chronic treatment with pimozide. In addition, the spinal cord and brain of mice revealed and increase in TDP-43 aggregation, but no change in microgliosis, was noted. Neuromuscular transmission was improved acutely. Pimozide is being tested in an ALS clinical trial based on our neuromuscular biomarker." @default.
- W1500527436 created "2016-06-24" @default.
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- W1500527436 date "2013-10-01" @default.
- W1500527436 modified "2023-09-25" @default.
- W1500527436 title "Chemical Genetic Screens for TDP-43 Modifiers and ALS Drug Discovery" @default.
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- W1500527436 doi "https://doi.org/10.21236/ada599884" @default.
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