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Genetic Correction of Mutant Huntingtin in Vivo

Award Number: R01NS094422
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: 09/01/2016
PERIOD OF PERFORMANCE END DATE: 08/31/2023

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Genetic Correction of Mutant Huntingtin in Vivo - The proposed research is intended to determine if a monogenetic disease such as Huntington's disease (HD) can be treated by using homologous recombination (HR) to genetically correct the disease containing allele in vivo. The approach will utilize a genome engineering system, CRISPR (Clustered Regulatory Interspaced Short Palindromic Repeats) delivered in vivo. In recent work in HD-iPSCs (induced pluripotent stem cells), we utilized homologous recombination to genetically correct the disease containing cells and found this completely reverses HD disease phenotypes. We have adapted the CRISPR technology to carry out genetic correction/expansion and have found very high levels of homologous recombination in human cells (Preliminary Results). The overall goal is to use this technology in vivo and carry out genetic correction of disease-containing mutations such as the CAG expansion in huntingtin (HTT). This work will serve as a proof of concept to demonstrate utility not only for monogenic neurodegenerative diseases but also for other types of genetic diseases. To achieve our goals we will carry out the following aims: Specific Aim 1. To demonstrate robust CRISPR-mediated recombination of the mutant HTT in human HD patient-derived neural cells using lentivirus; Specific Aim 2. To demonstrate robust CRISPR-mediated recombination in mouse models of HD expressing the human HTT protein using viral delivery; Specific Aim 3. To develop a protein-mediated delivery system using the nickase Cas9 D10A protein, gRNA and DNA to mediate homologous recombination in human-patient HD neural stem cells and HD mouse models. These studies will advance our understanding of how to perform genetic correction in cells derived from the brain. The successful demonstration of in vivo genetic correction of the disease allele in the brain would be a major leap forward in neuroscience.


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: 2024 ( Subtotal = -$6,053 )
2024	2020	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/25/2024	NON-COMPETING CONTINUATION	-$6,053
														Subtotal = -$6,053

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	9/16/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $424,375 )
2020	2020	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/27/2020	NON-COMPETING CONTINUATION	$424,375
														Subtotal = $424,375

Issue Date FY: 2019 ( Subtotal = $424,375 )
2019	2019	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	9/6/2019	NON-COMPETING CONTINUATION	$424,375
														Subtotal = $424,375

Issue Date FY: 2018 ( Subtotal = $424,375 )
2018	2018	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	9/21/2018	NON-COMPETING CONTINUATION	$424,375
														Subtotal = $424,375

Issue Date FY: 2017 ( Subtotal = $424,375 )
2017	2017	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/2/2017	NON-COMPETING CONTINUATION	$424,375
														Subtotal = $424,375

Issue Date FY: 2016 ( Subtotal = $424,375 )
2016	2016	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BOULEVARD	NOVATO	CA	94945	MARIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/18/2016	NEW	$424,375
														Subtotal = $424,375

Grand Total All Awards = $2,115,822

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Genetic Correction of Mutant Huntingtin in Vivo

Award Number: R01NS094422

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: 09/01/2016

PERIOD OF PERFORMANCE END DATE: 08/31/2023

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