Preclinical Characterization of CRAC Channel Inhibitors for the Treatment of Alzheimer's Disease

Vivreon BiosciencesLLCTrade StSan DiegoCAvivreonbiosciences@gmail com Vivreon BiosciencesNIA SBIRPASProject Summary Vivreon Biosciences is pleased to apply for NIA SBIR SolicitationPASVivreon Biosciences is an innovative life sciences company that is developing a series of novel small moleculeCachannel inhibitors for the treatment of Alzheimerandapos s diseaseADOur lead compound series achieves neuroprotection by an entirely new mechanisminhibition of Carelease activated CaCRACchannels to block microgliosisVivreon seeks NIA funding to bridge the gap between discovery and developmentWe will perform a series of functional safety pharmacology and in vitro efficacy screens to identify promising candidate compounds in our library of small molecule CRAC channel inhibitorsUpon successful completion of the programour preclinical candidate will be the first to specifically target the CRAC pathway for neuroprotection in ADthus comprising an entirely new tool in the battle against ADVivreon has discovered a lead compound series with oral bioavailability that penetrates into the central nervous systemCNSvery efficientlyshows no neurotoxicity in the Irwin test of CNS integrityand demonstrates neuroprotection in a mouse model of microgliosisexperimental autoimmune encephalitisThe lead series inhibits microgliosis by blocking CRAC channel activity with nM potencysuppressing Mlike NFB activitywhile preserving Mlike phagocytosisWe will now test select candidates from our lead compound series in innovative safety and efficacy screens using screening technology from patient derived induced pluripotent stem cellsiPSCsiPSCs will first be grown and differentiated into microHearts and screened for functional safety pharmacology to detect potential cardiac toxicity liabilitiesFinallyiPSCs from persons with Alzheimerandapos s disease will be differentiated into microglia like cells to monitor the anti neuroinflammatory capacity of our candidate drugsThe final aim for this proposal is the preliminary preclinical characterization of the first CRAC channel inhibitor for AD therapy and identification of key inflammatory cytokines that may be used as surrogate biomarkers for target engagement in future clinical studies Vivreon BiosciencesLLCTrade StSan DiegoCAvivreonbiosciences@gmail com Vivreon BiosciencesNIA SBIRPASProject Narrative Current Alzheimerandapos s diseaseADtherapies act on neurons only to alleviate symptoms of the disease without slowing disease progressionMicroglial associated genes are risk factors for ADand chronic microgliosis contributes to progressive neurodegeneration in ADVivreon Biosciences is testing candidate neuroprotective therapeutics in human AD microglia to explore biomarkers that will guide our future AD clinical approach