Innovative Delivery of siRNA across the Blood Brain Barrier

Project Summary Drug delivery across the blood brain barrier is a significant challenge in developing successful therapeutics for brain malignanciesDespite significant advances in developing small moleculespeptidesand nucleic acid treatment optionssuccessful delivery of these molecules to the brain diminishes their promiseWe propose a novel approach of delivering small interfering RNAsiRNAacross the blood brain barrier for therapeutic applicationsharnessing the body s natural microRNA delivery vehiclehigh density lipoproteinsHDL particles bind specifically to the scavenger receptor class B typeSR Band unload their core contents directly to the cytosol of cells bypassing the endo lysosomal pathway which facilitates delivery of cholesterol and phospholipids to steroidogenic tissues and the liverOur chief scientific collaborator has developed unique adaptations of this natural lipid delivery system to deliver diverse drugs and therapeutic agentsincluding therapeutic nucleic acidsvia reconstituted HDLrHDLnanoparticles particles with specified phospholipid and apolipoprotein content analogous to native HDLdemonstrating their ability to enter the brainAs an advantage over small moleculesthis lipoprotein formulation has a long circulating half lifedelivers therapeutic payloads directly to the cytosoland targets the SR Breceptorwhich is expressed on the BBB and enables transcytosis of the particle into the brainWhile our prior data demonstrating proof of concept rHDLmediated siRNA delivery is in SR Boverexpressing ovarian cancer cellsthere is strong evidence in the literature to support our proposal for rHDL particles crossing the BBB for efficient therapeutic siRNA deliveryAs an initial proof of concept studywe will target asparagine endopeptidaseAEPan enzyme recently discovered to cleave both APP and tauthe two key components of Alzheimer s Disease pathologyAEP has been demonstrated to be activated and elevated in human AD brains leading to increasedAand tau accumulationand progressive neurodegenerationA novel small molecule AEP inhibitor was recently developed that reduces tau and APP cleavageimproves long term potentiationand improves memory protection in transgenic AD mice upon oral administrationWhile these pre clinical results are encouragingthe safety and specificity have yet to be determined and this small molecule will likely face typical challenges for drug delivery to the brainshort residence time in circulation and low blood brain barrierBBBpermeabilityThusthere exists an urgent need to develop specific and effective AEP inhibition for AD treatmentThe focus of this proposal is to accomplish key milestones that will establish proof of concept BBB crossing drug delivery to the brainWe aim to designscreenand select a novel AEP siRNA for AD treatmentDelivery will be mediated via rHDL to determine biodistribution and measure AEP gene silencing effects in an AD mouse model Project Narrative Though siRNA gene silencing has great potential as a therapeutic strategy for neurological diseases and malignancieseffective delivery of therapeutic siRNA molecules to the central nerve system across the bloodbrain barrierBBBremains a significant challengeHerewe propose a strategy to utilize the BBB crossing features of reconstituted high density lipoproteinrHDLparticles to deliver a novel siRNA targeting asparagine endopeptidaseAEPa protease that cleaves both amyloid precursor protein and tau proteinfor the treatment of Alzheimer s DiseaseADBy evaluating the effect of AEP siRNA rHDL in both in vitro and in vivo AD modelsour approach and anticipated results may provide an effective solution to one of the major problems with systemic drug delivery to the brain