Discovery of new therapeutics for Huntingtons Disease through successive reversal of phenotypic signatures

Summary Huntingtonandapos s diseaseHDis a dominant autosomal neurodegenerative disease that is caused by an expansion of CAG repeats in the HTT locus that translates into an increase of poly glutaminepolyQrepeat in the Huntingtin protein HTTIt is estimated thatinAmericans suffer from HDDespite the fact that HTT was among the first disease causing genes to be cloned overyears agono therapy yet existsand HD remains an orphan diseaseThe discovery of any drug that can preventdelay the onsetor prolong life will have a major impact for HD patients and their familiesIn order to generate a human model of HDwe used CRISPR Casgenome editing tool in human Embryonic Stem CellshESCsto generatedistinct HD mutant isogenic lines that are genetically identical except for the length of their CAG expansionGlobal comparative transcriptome analysis in our CAG expanded isogenic linesallowed the discovery of a cluster ofgenes located on the chromosomethat are consistently shutdown in all HD linesWe found that the same cluster is also down regulated in human samplesThe presence of this signature in vivo validates the relevance of this readout as a marker of HDWe call this clusterHD cold spotMoreoverat the multicellular levelself organization of these lines into human neural structures unveiled previously unrecognized tissue specific differencesproviding a unique signature of the neuropathology underlying the diseaseThe fact that HTT is ubiquitously expressed and has pleiotropic activity has complicated the assignment of critical pathogenic function to mutant HTTWe make the hypothesis that an ideal therapeutic agent will rescue as many as possible of the different effects induced by mutant HTTA successful therapeutic candidate will therefore revert the different phenotypic signatures observed in our HD linesstarting with the rescue of HDspecific transcriptomic changestheHD cold spotwhich is the focus of this Phase Iup to complex multi cellular phenotypes arising through developmental self organization into neural structuresThe Phase I SBIR is focused on developing the initial High Throughput screening platform based on theHD cold spotIn Phase IIwe will combine this transcriptomic readout with tissue level defects observed in self organized neural structures to screenmolecules for phenotypic rescue and discover new leads for treating HD Our proposal will have a transformative impact on the drug discovery landscapedemonstrating how selforganized neural structures from human embryonic stem cells can be used for drug discovery and ultimately ameliorating the life of patients by finding new therapeutics for Huntingtonandapos s Disease ! !