Optimization of Novel Ryanodine Receptor Modulatory Compounds for Alzheimer's Disease

Abstract Summary Currentlythere are no effective treatments to preserve cognitive function in AD patients and the recent series of disappointing clinical trials highlight the need to explore alternative pathwaysTo this endNeuroLucent Incand its academic partnerRFUMSare developing small molecule compounds designed as allosteric modulators of the ryanodine receptorRyRa high conductance calcium channel in the ER membraneas candidates for clinical testingIn human AD patientsbrainsinduced neurons from AD patient fibroblastsand in AD mouse modelsincreased RyRisoform expression is observed in early disease stages across familial and sporadic casesIn neurons from AD mouse models and human samplesRyR evoked calcium release is significantly increased and directly contributes to synaptic dysfunction and lossincreased amyloid and tau pathologydisrupted memory functionand other AD defining featuresWe and others have demonstrated that treating AD mice with dantrolenea RyR channel stabilizerresulted in exciting therapeutic effectsThe combined results demonstrate normalized calcium signalingChakroborty et alaOule et alStutzmann et alnormal synaptic transmission and plasticityChakroborty et alarestored synaptic structure and integrityBriggs et alreduced Aand phospho tau levelsChakroborty et alaOule et alPeng et alrestored RyR isoform levelsChakroborty et alaOule et aland improved performance on memory testsOule et alPeng et alStutzmann labunpublished dataThese data support a strong case for stabilizing RyR functionwith a focus on RyRas a novel therapeutic strategy for ADThe objective of this study is to designtestand optimize compounds that will function as RyR negative allosteric modulatorsserving to suppress excessive calcium release while maintaining physiological functionsThe central hypothesis is that development and optimization of small molecule RyR stabilizers will generate therapeutic leads for clinical testing in early AD and MCI patientsand protect cognitive abilities through the preservation of calcium homeostasis and synaptic functionThis will be accomplished with the following AimsSynthesize and optimize RyRtargeted allosteric modulators for CNS targetsThis will use iterative medicinal chemistry procedures and ADME testing in collaboration with Sanford Burnham Prebys and WuXi AppTec CRO partnersOptimize biological efficacy of RyR compounds using rapid screening assays in cell culture systems and neurons from AD patients and miceInitial screening will use automated fluorometric testing of RyR evoked calcium signals in cultured cells and transformed neurons from AD patientsfollowed by in vivo treatment studies in AD miceThe significance to public health is the development of an effective and novel treatment for ADThe identification of a lead compound by NeuroLucent and positioning for IND filing would be the next stage following this STTR project NarrativeThe objective of this study is to develop a series of small molecule compounds for the purpose of stabilizing dysregulated calcium signaling in early stage AD patients and people at risk for converting to AD like dementiaThe rationale is based on findings that disruptions in ryanodine receptor mediated calcium signaling are a central component of AD pathogenesisandtreatment with compounds that modulate the ryanodine receptor provide broad spectrum therapeutic effects in human neurons from AD patients and in AD mouse modelsDeveloping these compounds through a small business academic partnership has a high potential for success in the clinic