Tau oligomer platform validation using lead series candidate in htau mice

TITLETau oligomer platform validation using lead series candidate in htau mice PROJECT SUMMARYSBIR Funding OpportunityAdvancing Research on Alzheimerandapos s DiseaseADand Alzheimerandapos s Disease Related DementiasADRDRRPASThe long term goal of this program is to develop a disease modifyingsmall molecule drug for Alzheimer s diseaseADand related tauopathiesThere is a critical unmet need for a disease modifying drug for ADChronic treatment strategies require economically feasible approaches such as small molecule drugsThis program is progressing to fill this need with a disease modifying drug thatif successfulwill have a tremendous impact on the more than five million Americans who currently have ADprojected to bemillion byand their caregiversand will help reduce the current cost of $billionprojected to be $trillion byto our nationIn the Ph II program the lead compound inhibited tau aggregation in transgenic mice expressing human tauhtaubest representing tau aggregation in AD using a preventive paradigmThis application is for testing the efficacy of the lead in JNPLmice that model tau pathology in frontotemporal dementia using both preventiveAimand therapeuticAimtreatment strategiesAdditionallythe lead will be tested in a therapeutic study in aged htau miceAimAnalysis of tau pathologytau aggregationhyperphosphorylation and misfoldingusing ELISAs and immunocytochemistry methodsand behavioral studies for the aged htau and JNPLmice will be performed to evaluate how mouse function tracks with reduction of tau pathologyJNPLmice develop hind limb paralysis as they age and will be evaluated for latency to fall using a rotarod apparatusAged htau mice develop cognitive deficits that will be characterized using the Barnes maze as a measure of spatial learning and memoryFor each JNPLstudy there will be three groups of micenper groupfeed vehiclemg kg ormg kg of compound milled in feedand for the htau study there will be four groupsnper groupbaseline cohortfeed vehiclemg kg ormg kg of compound in feedto sufficiently power the studiesCompound will be synthesized and formulated into feed prior to starting treatment for each study that will have staggered start timesThe length of treatment will be four months for each study that will start at different ages depending on the treatment paradigm and the characteristics of disease progression in the mice modelsThe in vivo studiesincluding behavioral characterization and analyses of tau pathologywill be performed independently by Peter DaviesPh Dand his laboratory at the Feinstein Institute for Medical ResearchManhassetNYResearchers will be blinded to treatment groups during treatment and for behavioral and biochemical analysesOligomerix will manage the projectperform additional analyses of mouse specimens with commercially available Abs for tau in parallel with its novel biomarker Abs for tau fragmentsand will analyze and report all dataThe primary endpoint for each study will be the reduction of insoluble tau with statistical significancethe secondary endpoints for the studies will be dose dependent reduction of insoluble taureduction of phosphorylated tauand reduction of cleaved tauand amelioration of motor or cognitive deficits in aged JNPLand htau micerespectively PROJECT NARRATIVE There is a critical unmet need for a disease modifying drug for ADof the ten leading causes of death in the United Statesonly AD cannot be preventedslowed or curedThis program is highly important because it is progressing to fill this need with a disease modifying drug thatif successfulwill have a tremendous impact on the more than five million Americans who currently have ADprojected to bemillion byand their caregiversand will help reduce the current cost of $billionprojected to be $trillion byto our nationAlzheimerandapos s AssociationAlzheimerandapos s Disease Facts and FiguresLong term treatment for chronic diseases such as AD requires economically feasible approaches such as small molecule drugsespecially for preventive and early therapeutic strategies