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Circuit-Specific Delivery of Large Cargo Across the Nervous Systems of Adult Mammals and Embryos via Novel Engineered Systemic Vectors

Award Number: DP1NS111369
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Circuit-Specific Delivery of Large Cargo Across the Nervous Systems of Adult Mammals and Embryos via Novel Engineered Systemic Vectors - Viviana Gradinaru, Caltech With the advent of technologies such as CRISPR/Cas9, genome engineering for both basic research and therapeutic applications is becoming reality. An outstanding challenge is the mean to safely and efficiently transfer large genomes to desired cells across life span. We have developed an in vivo Cre-based selection platform (CREATE) for identifying adeno-associated viruses (AAVs) that efficiently transduce genetically defined populations. We used CREATE to select for viruses that transduce the brain after intravascular delivery and found a vector that nonspecifically transduces most cells across the adult brain. Since the restrictive nature of the blood brain barrier presents a major impediment toward treating CNS disorders our discovery has the potential to enable exciting advances in gene editing/replacement via CRISPR-Cas or RNA interference to restore diseased CNS circuits if the needed level of efficiency and specificity can be engineered for diseased targets. We plan to enable such efforts by creating viral-based solutions to non-invasive whole- brain large cargo delivery across the blood-brain barrier from embryo to adult by: 1. Generating AAVs for cell-type and region specific gene delivery across the blood-brain- barrier, noninvasively via the bloodstream in the adult rodent for neurodegeneration applications. 2. Generate AAVs capable of transducing the developing brain in utero with a simple systemic injection to the pregnant dam for neurodevelopment research and therapy. 3. Increase the packaging capability of AAVs by about 2-fold to enable delivery of large genomes for gene therapy and research. 4. Enable non-invasive circuit specific deep brain modulation by the use of systemic vectors and genetically encoded activity modulators (e.g. by chemogenetics or others in development now). Longer term we plan, in our laboratory and also with collaborators, to contribute our neurotechnologies (including, in addition to viral vectors, tissue clearing and optogenetic control and imaging) towards elucidating maladaptive neural circuits that contribute to brain pathology in neurodegeneration and neurodevelopment.


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: 2025 ( Subtotal = -$1 )
2025	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/7/2025	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2023 ( Subtotal = $1,172,500 )
2023	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/23/2023	NON-COMPETING CONTINUATION	$1,172,500
														Subtotal = $1,172,500

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	9/15/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $1,172,500 )
2021	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	8/20/2021	NON-COMPETING CONTINUATION	$1,172,500
2021	2020	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	6/16/2021	NON-COMPETING CONTINUATION	$0
2021	2019	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/16/2021	NON-COMPETING CONTINUATION	$0
2021	2018	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/16/2021	NEW	$0
														Subtotal = $1,172,500

Issue Date FY: 2020 ( Subtotal = $1,172,500 )
2020	2020	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	9/2/2020	NON-COMPETING CONTINUATION	$1,172,500
2020	2019	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/9/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,172,500

Issue Date FY: 2019 ( Subtotal = $1,274,000 )
2019	2019	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	8/28/2019	NON-COMPETING CONTINUATION	$1,172,500
2019	2018	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/29/2019	NEW	$101,500
														Subtotal = $1,274,000

Issue Date FY: 2018 ( Subtotal = $1,071,000 )
2018	2018	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/20/2018	NEW	$1,071,000
														Subtotal = $1,071,000

Grand Total All Awards = $5,862,499

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Circuit-Specific Delivery of Large Cargo Across the Nervous Systems of Adult Mammals and Embryos via Novel Engineered Systemic Vectors

Award Number: DP1NS111369

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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