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

Award Number: R43AG061983
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2021

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Dual Intracellular and Extracellular Expression Technology (dIEE) for Alzheimer????????????????????????s Disease - 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 Aβ-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 Aβ 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = -$1,723 )
2022	2018	LARIX BIOSCIENCE LLC	1230 BORDEAUX DR	SUNNYVALE	CA	94089	SANTA CLARA	USA	Aging Research	000	1	2/24/2022	NEW	-$1,723
														Subtotal = -$1,723

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	LARIX BIOSCIENCE LLC	1230 BORDEAUX DR	SUNNYVALE	CA	94089	SANTA CLARA	USA	Aging Research	001	1	8/28/2020	NEW	$0
2020	2018	LARIX BIOSCIENCE LLC	1230 BORDEAUX DR	SUNNYVALE	CA	94089	SANTA CLARA	USA	Aging Research	000	1	8/13/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $224,981 )
2018	2018	LARIX BIOSCIENCE LLC	1230 BORDEAUX DR	SUNNYVALE	CA	94089	SANTA CLARA	USA	Aging Research	000	1	9/21/2018	NEW	$224,981
														Subtotal = $224,981

Grand Total All Awards = $223,258

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

Award Number: R43AG061983

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2021

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