Glycosaminoglycan-Interacting Small Molecule (GISMO) as Alzheimer's Therapeutics

Glycosaminoglycan Interacting Small MoleculeGISMOas Alzheimer s Therapeutics ABSTRACT The aim of this project is to develop a noveldisease modifying oral therapeutic agent for the treatment of Alzheimer s DiseaseIn the first phase of this projectwe identified promising lead compounds via proprietary Glycosaminoglycan Interacting Small MoleculeGISMOdrug discovery platformGISMOs are based on a novel hypothesis for the cause of Alzheimer s Disease and provide a new therapeutic principle for the treatment of this devastating neurodegenerative diseaseAlzheimer s Disease is associated with the pathological aggregationi eamyloidosisof amyloid beta peptidesAbeta peptidesAccording to GISMO hypothesisAbeta aggregation is necessary but not sufficient to cause Alzheimer s DiseaseRatherexcessive accumulation and storage of a class of complex polysaccharidesglycosaminoglycansGAGsin the lysosomes of nerve cells is another essential component of the pathological process leading to Alzheimer s DiseaseIn our current work we show that GISMOs directly target heparan sulfate GAGsHS GAGsinhibit Abetabinding to HS GAGsand have potent biological activity in at several assays relevant to amyloidosis in nerve cell culturesSpecificallywe identified GISMO lead compounds that inhibit uptake of Abeta by neuronal cellsand display potent neuroprotective properties against Abeta peptidesAbetaand AbetaThis is the first report of Abeta HS GAG inhibitorsGISMOshaving potent neuroprotective properties against toxic Abeta peptidesIn addition to reducing the toxic accumulation of amyloid aggregates inside nerve cellsGISMOs may also slow the progression of Alzheimer s disease by inhibiting the spread of amyloid proteopathic seeds in brain tissueThe identified lead compounds conform to Lipinski rules and display selectivity and other drug like propertiesThese results provide in vitro target validation as well as justification for further development of GISMO compounds as Alzheimer s Disease therapeuticsIn Specific Aimwe will assess the lead compounds for their pharmacokinetic profilesoral bioavailabilityblood brain barrier penetrationand establish their maximum tolerated doseMTDIn Specific Aimwe will test the two best lead compoundsselected from Aimfor their efficacy in two transgenic mouse models of ADWe will treat transgenic AD mice with two compounds at three doses for each compound and evaluate the effectiveness of treatment using standard tests for learning and memoryas well as biochemicalhistopathologicaland immunochemical methodsIn Specific Aimwe will perform further preclinical testing of the selected development candidateThe successful completion of these studies will allow us to select a development candidate for preclinical developmenttowards an INDand clinical trials