Targeting Bioenergetic Flux for Alzheimer's Disease Management

PROJECT SUMMARYBioenergetic dysfunction occurs in Alzheimer s diseaseADand represents a potential AD therapeutic targetFor these reasonswe founded AerobyxLLCThe goal of Aerobyx is to develop drugs that specifically target brain bioenergetic fluxesand to use those drugs to treat persons with ADOur strategy emphasizes fundamental biochemical principles such as the law of mass actionand additionally exploits redox ratiosin particular NADNADH couplingthat gate some bioenergetic fluxesOur overarching hypothesis is that enhancing brain respiration fluxglycolysis fluxor both will benefit AD patientsThis phase I SBIR will specifically advance development of two of our lead compoundsboth of which are esters of oxaloacetateOAAOur interest in OAA derives from observations that OAA can concomitantly enhance both glycolysis and respiration fluxesand a study performed in mice that found OAA activated brain mitochondrial biogenesis promoting proteinsenhanced activity of the brain insulin signaling pathwayreduced neuroinflammation markersand increased hippocampal neurogenesisAs OAA is unstable in solutionwe stabilized it through esterification at its carboxyl endsto molecules that can independently support bioenergetic metabolismUnder in vitro conditions these compounds perform as predictedand in cultured cells enhance respirationTo develop further these compounds for clinical usewe will now increase compound synthesis to levels that can support in vivo studiesand obtain in vivo pharmacokinetic and pharmacodynamic dataAccordinglywe will dose mice with both compoundsmeasure bloodplasmaand brain levels of the parent compounds and their metabolitesand assess brain target engagementData generated during this phase I SBIR will inform a phase II SBIR project in which we perform comprehensive animal toxicity studiesand determine the effects of our compounds in an AD transgenic mouse model PROJECT NARRATIVEBioenergetic dysfunction occurs in Alzheimer s diseaseADand represents a potential AD therapeutic targetFor these reasonsAerobyxLLC intends to developfor the treatment of ADtwo novel compounds that enhance bioenergetic fluxes