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Ultrasound-Controlled in Vivo Gene Editing with Photoswitchable CRISPR-CasMINI

Award Number: R01NS142873
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: 08/11/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Ultrasound-Controlled in Vivo Gene Editing with Photoswitchable CRISPR-CasMINI - ABSTRACT Expression of CRISPR-Cas proteins with blood-brain-barrier (BBB)-crossing adeno-associated virus (AAV) enables non-invasive editing or regulation of specific genes in specific cell types of the brain, and thus holds immense promise for basic research and disease treatment. However, unregulated CRISPR-Cas expression increases the risk of off-target genome modifications. If we can engineer photoregulation into CRISPR systems, then both spatial and temporal control would be possible in the brain. However, current systems for photocontrol of CRISPR-Cas activity are too large for packaging in AAV, and current methods for light delivery deep into the brain are invasive and tissue-damaging. In this project, we tackle both of these limitations, first by designing and optimizing a single-chain photoswitchable CasMINI protein (psCasMINI) and second by designing and optimizing mechanoluminescent nanotransducers (MLNTs) which can produce light when stimulated with focused ultrasound (FUS) deep within tissue. With preliminary data demonstrating proof of concept for psCasMINI and FUS stimulation of MLNTs, we propose now to use these new methods to realize noninvasive cell-type-specific FUS-localized gene editing in the brain using brain-targeting AAV vectors. Our proposed specific aims are (1) Optimizing and characterizing the efficacy and specificity of light-induced psCasMINI, (2) Optimizing ultrasound-activated light sources for FUS-mediated gene editing, and (3) Demonstrating non-invasive localized on-demand inactivation of an endogenous gene that is the target of anti-epileptic treatments. This project represents a close collaboration between two groups with complementary expertise, one in the engineering of photoregulatable proteins and expression in the brain, and the other in the engineering of materials that interact with light and sound. The successful completion of this project will establish ultrasound- induced light generation and transBBB delivery of photoswitchable CasMINI as a powerful method to perform cell- and region-specific gene editing with minimal invasiveness, improving the safety and versatility of CRISPR- based gene editing.


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 = $618,680 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/10/2026	NEW	$618,680
														Subtotal = $618,680

Grand Total All Awards = $618,680

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Ultrasound-Controlled in Vivo Gene Editing with Photoswitchable CRISPR-CasMINI

Award Number: R01NS142873

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: 08/11/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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