Screening for rAAV transduction enhancers

ABSTRACT Recombinant adeno associated virusrAAVis a promising gene delivery vector for therapeutic and vaccine applicationsbut its low transduction efficacy currently limits its utilityThe primary reasons for low transduction efficacy are as followsiinefficient trafficking of the rAAV genome to the nucleusiiinefficient host cell mediated synthesis of double stranded DNA from the single stranded genomeandiiiToll like receptorTLRresponsesThe goal of this proposal is to identify small molecules that increase the transduction efficacy of rAAV transduction by modulating any one of the barriersOne immediate application will be the use of these compounds in the rAAV based gene therapy against HIV developed in DrMichael Farzan s laboratory at The Scripps Research InstituteThe rAAV vector expresses an antibody like immunoadhesineCDIga fusion of CDIg with a small CCRmimetic sulfopeptidewhich binds to the HIVsimian immunodeficiency virusSIVenvelope glycoprotein and protects macaques from infectionIncreased transduction efficacy will decrease both the cost of treatment and the adaptive immune response to the viral capsid and expressed transgene that limits the use of rAAV vectors in humansHoweverthe significance of our studies goes beyond HIVprophylaxisThese small molecules will be useful for other rAAV based vaccines and therapeuticssuch as vaccines developed for influenzamalariaand dengue infectionor for the long term delivery of biologicsIn Phase Iwe willidevelop a high throughput screeningHTSassay to identify compounds that enhance rAAV transductioniiidentify transduction enhancersiiibroadly evaluate the mode of actionand prioritize hits for a Phase II studyPromising scaffolds will be subjected to a rational drug design program in Phase IIand will be advanced to IND enabling studies