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

Dual Intracellular and Extracellular Expression TechnologydIEEfor Alzheimerandapos s Disease AbstractMultiple intertwined mechanisms contribute to the pathogenesis of Alzheimerandapos s DiseaseADa devastating neurodegenerative illness afflicting overmillion AmericansAggregates of the microtubule associated protein tau represent a major pathological finding in AD and other neurodegenerative tauopathies and unlike extracellular Aamyloid plaquescorrelate well with progressive cognitive declineExposure of the N terminal phosphatase activating domainPADmay be one of the earliest and most consequential conformational changes of tauIntracellular microinjection of recombinant tau near the synapse exposes PADand a peptide corresponding to the PAD itself leads to synaptic dysfunctionWhile tau is normally localized intracellularlyduring AD a positive feedback loop with Acan spread damage extracellularly throughout the brainPathological tau then creates two challenges for a potential therapeuticablock intracellular initiation activity and bclear toxic extracellular tau 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 tau PAD single chain intrabodyiAbcombined with a secreted extracellular anti Tau N TerminalTNTantibodysAbOur novel dual intrabody antibody approach employs proprietary dual Intracellular and Extracellular Expression technologydIEEWe hypothesize that the combined effect of the anti tau intrabody and secreted antibody will reduce tau mediated pathology with concomitant improvement of ADIn 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 construct the vectorsand test their expression of TNTiAb and TNTsAb in vitro and in the brains of recipient miceWe are optimistic that our AAV dual expression system for delivery of anti tau PAD domain intrabodies and antibodies to the brains of affected patients will provide a novel restorative therapy for AD NarrativeWe will develop a gene therapy approach to deliver a dual intracellular extracellular therapeutic anti tau antibody to the brains of Alzheimerandapos s disease patientsOur approach may be extendable to other neurodegenerative diseases that involve pathological changes in the tau protein