Add Mnda Byline with airSlate SignNow

Add mnda byline

despite considerable research efforts into the basic pathophysiology of als the translational pipeline has produced few successful drugs with previous support from the mnda we generated mouse embryonic stem cells expressing full length human wild type and m337v tdp-43 motor neurons can be differentiated from these cells and used as a platform for high throughput screening to identify potential new drugs for als with the oxford target discovery institute we performed a screen using a library of fda approved drugs to identify those which could improve survival of mutant motor neurons following oxidative insult we tested resilient fluorescence as a readout of motor neuron survival and confirmed that mutants containing motor neurons are significantly more sensitive to oxidative stress than controls 24 hours following a one hour insight with sodium arsenide the protocols for the primary screen and secondary validation are shown schematically in a and b all compounds within the pharmacom 1600 collection have reached clinical evaluation and demonstrate biological activity against known targets and many are available on the market putative hits were identified from our original screen of these six have continued to show improved survival of mutant motor neurons after oxidative stress in both dose response testing and in secondary validation where we've tested concentrations designed to elicit a survival response which is calculated from the dose curves in previously published work we've shown that m337v motor neurons display reduced survival and a reduction in the number of stress granules per cell after oxidative stress treatment of mutant motor neurons with each candidate drug rescued the number of stress granules per cell as part of our continuing orthogonal testing drug candidates currently demonstrate little detrimental effect on cell morphology of wild-type or mutant motor neurons as measured here by their effect on cell body area the schematics shows our currently proposed drug discovery pipeline promoting mutant motor neuron survival restoration of differential phenotypes between wild-type and mutant motor neurons increases the likelihood that candidate drugs will pass to phase 2 testing our ongoing experiments are ended exploring the combinatorial effects of the candidate drugs on motor neuron survival and improving our survival assay as a drug discovery platform drugs will be further validated through analysis of phenotypic and transcriptional changes in our mouse and human models finally we'd like to thank the generous financial support of both the mnda and the my names dottie foundation thank you