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

Award Number: R43NS113704
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2021

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Dual Intracellular and Extracellular Expression Technology (dIEE) for Parkinson?s Disease - Dual Intracellular and Extracellular Expression Technology (dIEE) for Parkinson’s Disease Abstract Alpha-synuclein (a-syn) is a key player in the pathogenesis of Parkinson's Disease (PD), a devastating neurodegenerative illness that will afflict over 920,000 Americans by 2020. Oligomers and aggregates of this presynaptic-vesicle-associated protein characterize major pathological findings in PD that correlate well with progressive motor neuron functional decline. While a-syn is normally localized intracellularly at synapses, during PD, oligomeric a-syn can spread damage extracellularly in a defined path through the brain in a prion-like manner, where the altered conformation of oligomeric a-syn catalyzes creation of increased aberrant a-syn. Pathological a-syn then creates at least three challenges for a potential therapeutic: a) block intracellular initiation-activity, b) clear intracellular pathological a-syn, and c) clear toxic extracellular a-syn 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-oligomeric a-syn single-chain intrabody (iAb) combined with a secreted extracellular anti-a-syn N-Terminal 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-a-syn intrabody and secreted antibody will reduce alpha-synuclein-mediated pathology with concomitant improvement of PD. 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 identify potent anti-oligomeric human a- syn antibodies, construct the vectors, and test their expression in vitro and in the brains of recipient mice. We are optimistic that our AAV dual expression system for simultaneous delivery of anti-oligomeric-a-syn intrabodies and antibodies to the brains of affected patients will provide a novel restorative therapy for PD.


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 = $0 )
2022	2019	LARIX BIOSCIENCE LLC	1230 BORDEAUX DR	SUNNYVALE	CA	94089	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/16/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $225,000 )
2019	2019	LARIX BIOSCIENCE LLC	1230 BORDEAUX DR	SUNNYVALE	CA	94089	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/29/2019	NEW	$225,000
														Subtotal = $225,000

Grand Total All Awards = $225,000

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

Award Number: R43NS113704

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2021

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