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Cell type selective viral tools to interrogate and correct non-human primate and human brain circuitry

Award Number: UH3MH120095
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Cell type selective viral tools to interrogate and correct non-human primate and human brain circuitry - Abstract: Many cell types together assemble the functional circuitry of the human brain. For over a century, neuroscientists have categorized brain cell types by their features, including shape, position, physiology, molecules, and function. Single cell transcriptomics studies are now defining molecular cell types at a resolution not previously possible, uncovering a taxonomy of hundreds to thousands of brain cell types. These studies have also revealed dramatic differences in molecular signatures of homologous cell types across species, showing decisively that the difference between mouse and human brain is not simply the total number of neurons. However, the function of each cell class or type in brain circuitry, and dysfunction in disease, is only beginning to be evaluated. To characterize the roles of human brain cell classes in normal function and disease, it is critical that tools be developed to allow genetic access to cell classes in vivo. Such tools would enable precise therapeutic gene delivery to brain cell classes, permitting targeted treatment for class-specific etiologies like some epilepsies. Few genetic tools are available to mark and manipulate cell classes and types in non-genetically tractable species like human and non-human primate (NHP). Viruses including adeno-associated viruses (AAVs), containing cell class and type selective enhancers can be leveraged to gain genetic access to, and drive gene expression in specific brain cell classes in these species. We have initiated a project through the BRAIN Initiative to generate and validate reporter AAVs to mark specific cell classes in the mouse cortex in vivo and in human neocortical tissue ex vivo. Our groups have engineered AAV vectors and optimized capsids to access neurons and express transgenes in many discrete cell classes and types in mouse and primate. New and improved AAV tools promise to fuel human brain scientific discovery and clinical progress, but one impediment has been the costly and time-consuming process of validating new vectors in primates. We present three Aims to translate these promising new AAV vectors into a high-value set of primate-optimized tools that could eventually be used for gene therapies in humans. First, we will develop a platform for screening AAV vectors in NHP ex vivo brain slices, followed by individual validation of promising vectors in NHP in vivo and human ex vivo brain slice cultures. Second, we will identify optimal AAV capsids to: a) support widespread NHP neuronal transduction in vivo when applied intravenously or to cerebrospinal fluid (CSF), two preferred routes of delivery for human CNS gene therapy, and b) support AAV transduction of human primary brain tissue ex vivo. Third, we will perform proof-of-concept experiments using cell class-selective vectors to express a therapeutic transgene in defined classes to treat a severe and intractable form of childhood epilepsy called Dravet syndrome (DS). These experiments represent a significant step towards converting cell class-selective AAVs into first-in-class viral tools optimized for in vivo NHP brain studies and human gene therapy applications.


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: 2026 ( Subtotal = -$161,248 )
2026	2025	ALLEN INSTITUTE	615 WESTLAKE AVE N	SEATTLE	WA	98109	KING	USA	Mental Health Research Grants	000	5	5/27/2026	NON-COMPETING CONTINUATION	-$161,248
														Subtotal = -$161,248

Issue Date FY: 2025 ( Subtotal = $785,732 )
2025	2025	ALLEN INSTITUTE	615 WESTLAKE AVE N	SEATTLE	WA	98109	KING	USA	Mental Health Research Grants	000	5	4/8/2025	NON-COMPETING CONTINUATION	$785,732
														Subtotal = $785,732

Issue Date FY: 2024 ( Subtotal = $901,932 )
2024	2024	ALLEN INSTITUTE	615 WESTLAKE AVE N	SEATTLE	WA	98109	KING	USA	Mental Health Research Grants	001	4	7/24/2024	EXTENSION WITH OR WITHOUT FUNDS	$0
2024	2024	ALLEN INSTITUTE	615 WESTLAKE AVE N	SEATTLE	WA	98109	KING	USA	Mental Health Research Grants	000	4	2/8/2024	EXTENSION WITH OR WITHOUT FUNDS	$901,932
														Subtotal = $901,932

Grand Total All Awards = $1,526,416

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Cell type selective viral tools to interrogate and correct non-human primate and human brain circuitry

Award Number: UH3MH120095

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/01/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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