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Gene editing in the brain with CRISPR-PEG

Award Number: R01MH125979
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Gene editing in the brain with CRISPR-PEG - CRISPR-based gene editing has the potential to revolutionize the treatment of genetic brain disorders. However, complications with brain delivery have limited the utility of CRISPR-based therapeutics. To address this critical need, we have developed a new gene editing delivery vehicle, termed CRISPR-PEG, which is composed of Cas9 RNP conjugated to polyethylene glycol (PEG). CRISPR-PEG has tremendous promise as a delivery vehicle because of its excellent biocompatibility, the well-established clinical track record of PEG, and its enhanced tissue diffusion capability in comparison to nanoparticles. Our preliminary results demonstrate that CRISPR-PEG delivers and edits neurons efficiently in the motor cortex or striatum in mice; after an intracranial injection, neurons were edited with a high specificity (45~85%). Notably, CRISPR-PEG also edited neurons in the olfactory bulb after intranasal administration. These exciting results demonstrate that CRISPR-PEG has great potential as bio-tool, and as a platform for developing therapeutics. In this proposal we will test our novel delivery vehicle CRISPR-PEG in fragile X syndrome (FXS). We have selected FXS as a test bed for CRISPR-PEG because it is the most common inherited cause of intellectual disability with no treatment available. In addition, FXS has a monogenic cause, namely expanded CGG repeats>200 and hypermethylation in the FMR1 promoter region, which causes silencing of the fragile X mental retardation 1 (FMR1) gene. Therefore, the central objectives of this proposal are (1) to test CRISPR-PEG in brain disorders by targeting FXS-associated genes, and (2) to develop new CRISPR-PEG variants with improved diffusion and efficiency. The central hypothesis is: the novel non-viral delivery vehicle CRISPR- PEG will deliver Cas9 RNPs into the brain, efficiently edit FXS-associated genes in neurons, and rescue mice from multiple FXS-associated phenotypes. The central objective will be accomplished by completing the following specific aims. Specific Aim 1. Knock down mGluR5 using CRISPR-PEG in the mouse model of FXS as proof of principle. Specific Aim 2. Reactivate FMR1 gene expression using CRISPR-PEG. Specific Aim 3. Develop CRISPR-PEGs that diffuse throughout the brain and edit brain tissue efficiently. At the completion of this proposed study, we will have developed an efficient strategy for gene editing neurons using a novel non-viral delivery vehicle CRISPR-PEG. Our proposed studies are significant because the results will provide the basis for developing therapeutics for FXS and fragile X-associated disorders caused by FMR1 deficiency. Moreover, we will develop a non-viral-based vehicle that can edit large volumes of brain tissue after a single injection. The experiments in this proposal are highly innovative because we will have developed an efficient and safe non-viral delivery vehicle, which will greatly advance the field of neuroscience and CRISPR-based therapeutics.


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 = $667,668 )
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Mental Health Research Grants	000	5	2/13/2025	NON-COMPETING CONTINUATION	$567,518
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Mental Health Research Grants	001	5	9/18/2025	NON-COMPETING CONTINUATION	$100,150
														Subtotal = $667,668

Issue Date FY: 2024 ( Subtotal = $671,929 )
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Mental Health Research Grants	001	4	8/14/2024	NON-COMPETING CONTINUATION	$67,193
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Mental Health Research Grants	000	4	1/24/2024	NON-COMPETING CONTINUATION	$604,736
														Subtotal = $671,929

Issue Date FY: 2023 ( Subtotal = $608,458 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Mental Health Research Grants	000	3	1/27/2023	NON-COMPETING CONTINUATION	$608,458
														Subtotal = $608,458

Issue Date FY: 2022 ( Subtotal = $646,076 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Mental Health Research Grants	001	2	6/21/2022	NON-COMPETING CONTINUATION	$64,608
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Mental Health Research Grants	000	2	1/21/2022	NON-COMPETING CONTINUATION	$581,468
														Subtotal = $646,076

Issue Date FY: 2021 ( Subtotal = $694,396 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Mental Health Research Grants	001	1	5/7/2021	NEW	$68,075
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Mental Health Research Grants	000	1	3/25/2021	NEW	$626,321
														Subtotal = $694,396

Grand Total All Awards = $3,288,527

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Gene editing in the brain with CRISPR-PEG

Award Number: R01MH125979

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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