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Mesenchymal Stem Cell Derived Extracellular Vesicles for Traumatic Brain Injury

Award Number: R01NS106907
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: 06/15/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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Mesenchymal Stem Cell Derived Extracellular Vesicles for Traumatic Brain Injury - Project Summary The goal of the proposed studies is to develop an efficient human mesenchymal stem cell (hMSC)-derived extracellular vesicle (EV) therapy for improving brain function in both acute and chronic phases after a traumatic brain injury (TBI). Studies in the previous funding period showed that a single intranasal (IN) administration of hMSC-EVs 90 minutes after TBI leads to better brain function. Such effects were associated with the inhibition of the nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 (NLRP3) inflammasome-p38 mitogen-activated protein kinase (p38/MAPK) pathway and better hippocampal neurogenesis. This renewal application proposes studies on the efficacy of hMSC-EVs with delayed administration in the acute phase or administration in the chronic phase after a TBI. Additional studies will identify highly enriched miRNAs mediating robust antiinflammatory effects within the hMSC-EVs cargo and test hMSC-EVs loaded with specific miRNAs for their ability to mediate robust therapeutic effects in the chronic phase of TBI. Specific Aim 1 studies will investigate whether delayed IN administrations of hMSC-EVs in the acute phase of TBI would lead to better cognitive and mood function by restraining the progression of acute neuroinflammation into a chronic state and maintaining better hippocampal neurogenesis. hMSC-EVs will be administered to young adult mice 4 or 24 hours post-TBI when acute neuroinflammatory and neurodegenerative processes are active. To understand mechanisms, the studies will also test hMSC-EVs with a knockdown of select antiinflammatory miRNAs that are highly enriched in their cargo. Specific Aim 2 studies will examine whether IN administrations of hMSC-EVs in the chronic phase after TBI would improve cognitive and mood function by modulating chronic neuroinflammation. hMSC-EVs will be given to young adult mice one-month post-TBI when chronic neuroinflammation and cognitive and mood impairments are already present. Specific Aim 3 studies will analyze whether loading select miRNAs into hMSC-EVs cargo enhances their antiinflammatory effects and promotes better cognitive and mood function when administered in the chronic phase after a TBI. Individual miRNAs with antiinflammatory properties (miR-30e-3p, miR-let-7c-5p, miR-20b-5p, miR-24-3p) will be loaded into hMSC-EVs and administered to young adult mice one-month post-TBI. In all Specific Aims, the studies will rigorously measure hMSC-EVs administration-mediated effects on the transcriptomic signature of activated microglia and reactive astrocytes via single-cell RNA sequencing, the activation of chronic NLRP3-p38/MAPK and cyclic GMP-AMP synthase (cGAS)-the stimulator of interferon genes (STING) signaling pathways via molecular assays, hippocampal neurogenesis, and cognitive and mood function. The proposed translational research studies are highly relevant to developing an allogeneic, off-the-shelf, hMSC-EV therapy in acute and chronic phases after a TBI.


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 = $584,405 )
2025	2025	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	7/28/2025	COMPETING CONTINUATION	$584,854
2025	2022	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	10/15/2024	NON-COMPETING CONTINUATION	-$449
														Subtotal = $584,405

Issue Date FY: 2022 ( Subtotal = $562,924 )
2022	2022	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/13/2022	NON-COMPETING CONTINUATION	$562,924
														Subtotal = $562,924

Issue Date FY: 2021 ( Subtotal = $573,950 )
2021	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/26/2021	NON-COMPETING CONTINUATION	$573,950
														Subtotal = $573,950

Issue Date FY: 2020 ( Subtotal = $577,012 )
2020	2020	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/8/2020	NON-COMPETING CONTINUATION	$577,012
														Subtotal = $577,012

Issue Date FY: 2019 ( Subtotal = $581,289 )
2019	2019	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/23/2019	NON-COMPETING CONTINUATION	$581,289
2019	2019	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/27/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $581,289

Issue Date FY: 2018 ( Subtotal = $590,351 )
2018	2018	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/5/2018	NEW	$590,351
														Subtotal = $590,351

Grand Total All Awards = $3,469,931

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Mesenchymal Stem Cell Derived Extracellular Vesicles for Traumatic Brain Injury

Award Number: R01NS106907

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: 06/15/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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