Dual Intracellular and Extracellular Expression Technology (dIEE) for Parkinson's Disease

Dual Intracellular and Extracellular Expression TechnologydIEEfor Parkinson s Disease AbstractAlpha synucleinsynis a key player in the pathogenesis of Parkinsonandapos s DiseasePDa devastating neurodegenerative illness that will afflict overAmericans byOligomers and aggregates of this presynaptic vesicle associated protein characterize major pathological findings in PD that correlate well with progressive motor neuron functional declineWhilesyn is normally localized intracellularly at synapsesduring PDoligomericsyn can spread damage extracellularly in a defined path through the brain in a prion like mannerwhere the altered conformation of oligomericsyn catalyzes creation of increased aberrantsynPathologicalsyn then creates at least three challenges for a potential therapeuticablock intracellular initiation activitybclear intracellular pathologicalsynand cclear toxic extracellularsyn to prevent progressionTo address these problemswe have designed a recombinant adeno associated viralAAVvector to achieve long termstable central nervous systemCNSdelivery of an antibodyThis vector will simultaneously deliver an intracellular anti oligomericsyn single chain intrabodyiAbcombined with a secreted extracellular antisyn N Terminal antibodysAbOur novel dual intrabody antibody approach employs proprietary dual Intracellular and Extracellular Expression technologydIEEWe hypothesize that the combined effect of the antisyn intrabody and secreted antibody will reduce alpha synuclein mediated pathology with concomitant improvement of PDIn additionAAV delivery addresses the blood brain barrierBBBproblem of systemic antibody therapy and represents a novel and potentially practical approach for the treatment of additional neurodegenerative diseasesIn Phase Iwe will identify potent anti oligomeric humansyn antibodiesconstruct the vectorsand test their expression in vitro and in the brains of recipient miceWe are optimistic that our AAV dual expression system for simultaneous delivery of anti oligomericsyn intrabodies and antibodies to the brains of affected patients will provide a novel restorative therapy for PD NarrativeWe will develop a gene therapy approach to deliver a dual intracellular extracellular therapeutic anti alphasynuclein antibody to the brains of Parkinsonandapos s disease patientsOur approach may be extendable to other related neurodegenerative diseases that involve pathological changes in the alpha synuclein protein that are associated with Lewy body formation