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

Larix Bioscience, Llc, Sunnyvale CA

Investigators

Abstract

Dual Intracellular and Extracellular Expression Technology (dIEE) for Alzheimer's Disease Abstract Multiple intertwined mechanisms contribute to the pathogenesis of Alzheimer's Disease (AD), a devastating neurodegenerative illness afflicting over 5 million Americans. Aggregates of the microtubule-associated protein tau represent a major pathological finding in AD and other neurodegenerative tauopathies and unlike extracellular A?-amyloid plaques, correlate well with progressive cognitive decline. Exposure of the N-terminal phosphatase-activating domain (PAD) may be one of the earliest and most consequential conformational changes of tau. Intracellular microinjection of recombinant tau near the synapse exposes PAD, and a peptide corresponding to the PAD itself leads to synaptic dysfunction. While tau is normally localized intracellularly, during AD a positive feedback loop with A? can spread damage extracellularly throughout the brain. Pathological tau then creates two challenges for a potential therapeutic: a) block intracellular initiation-activity and b) clear toxic extracellular tau to prevent progression. To address these problems, we have designed a recombinant adeno-associated viral (AAV) vector to achieve long-term, stable central nervous system (CNS) delivery of an antibody. This vector will simultaneously deliver an intracellular anti-tau PAD single-chain intrabody (iAb) combined with a secreted extracellular anti-Tau N-Terminal (TNT) antibody (sAb). Our novel dual intrabody/antibody approach employs proprietary dual Intracellular and Extracellular Expression technology (dIEE). We hypothesize that the combined effect of the anti-tau intrabody and secreted antibody will reduce tau-mediated pathology with concomitant improvement of AD. In addition, AAV-delivery addresses the blood brain barrier (BBB) problem of systemic antibody therapy and represents a novel and potentially practical approach for the treatment of additional neurodegenerative diseases. In Phase I, we will construct the vectors, and test their expression of TNT1-iAb and TNT1-sAb in vitro and in the brains of recipient mice. We 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.