Microparticle Therapy for Cerebral Amyloid Angiopathy

ABSTRACTCerebral Amyloid AngiopathyCAAa microvasculopathy in which beta amyloidAaccumulates in the walls of cerebral blood vesselsis associated with vascular fragility and bleeding secondary to blood vessel wall breakdownCAA is especially deleterious to vascular smooth muscle cellsVSMCCAA is found inof AD casesincreases hemorrhagic stroke riskand is exacerbated by amyloid immunotherapy thereby compromising this promising AD therapeuticThere is no effective therapy for CAADespite the prevalence of CAA in AD and the fact that AD and CAA are different diseasesCAA is often overlooked in AD studies as Ahas been widely presumed to be responsible for the VSMC loss in the walls of Aladen vesselsVSMC loss in CAA occurs due to formation of the complement systemandapos s cytolytic membrane attack complexMACin the tunica media of Aladen CAA blood vesselsBased on this discoveryour goal is to develop a first ever therapeutic for CAA based on inhibition of MAC formation which we hypothesize will prevent CAA induced vascular fragilityWe plan to target inhibition of MAC formation in the walls of Aladen CAA blood vesselsas opposed to systemic MAC inhibitiondue to the importance of MAC for immune protection against microbial infectionWe propose asmartnanoparticleSNPmade of depyrogenated chitosan that selectively targets cerebrovascular Adeposits to deliver an encapsulated CDplasmid whose expression abrogates the formation of MACWe have developed a technique to depyrogenate chitosan that enables internal placement since previous chitosans are contaminated with endotoxinsThese contaminants interfere with plasmid transfection and gene expressionOur chitosan depyrogenation technique is based on the application of nitrogen plasmathe same technology employed to decontaminate potential anthrax letters sent to CongressWe are asking for a two year phase I SBIR grant since six months is too short of a time to accomplish our three specific aimsThese aims areTo establish successful transfection of primary human cerebral vascular smooth muscle cellsHCVSMCswith chitosan gene containing microparticlesInduce surface expression of CDin HCVSMCs via microparticle transfection andEstablish successful protection of CDtransfected cells from MAC initiated cell lysis NARRATIVEOur goal is to develop a therapy for the microvasculopathy Cerebral Amyloid AngiopathyCAAbased on microparticle gene delivery of the complement regulator CDThere is increasing evidence that a complement mediated attack on brain microvascular cells plays a significant role in the pathogenesis of CAAOptimization of the chitosan mediated gene delivery system and determination of the CDprotective effect will be studied with in vitro cell cultures