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Engineered extracellular vesicles as a targeted drug delivery system for multiple sclerosis

Award Number: F31NS120590
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Engineered extracellular vesicles as a targeted drug delivery system for multiple sclerosis - Abstract The ultimate goal of this F31 Ruth L. Kirchstein NRSA is to request support to address a fundamental gap in knowledge preventing engineering of efficacious drug delivery vehicles for progressive multiple sclerosis (PMS). PMS is a common, debilitating neurodegenerative disease that causes widespread demyelination in the central nervous system. There are currently no therapies that reliably remediate the advance of PMS, but an emerging strategy is to promote recovery by initiating differentiation of oligodendrocyte progenitor cells (OPCs) to oligodendrocytes, the myelin producing cells depleted in PMS. Current drug delivery techniques to achieve remyelination are either poorly efficacious or highly invasive, major impediments to clinical translation. An effective remyelinating therapeutic for PMS must cross the intact blood-brain barrier (BBB) and then target OPCs. This proposal focuses on the synthesis and testing of engineered extracellular vesicles (eEVs) as a drug delivery vehicle to accomplish these feats. Natural EVs have been shown to both target specific cells/tissues and also cross endothelial barriers. However, due to their immense functional heterogeneity, these qualities do not occur in the same EVs. Although a population of EVs that efficiently targets OPC has been identified, the best EV population and key proteins that promote BBB crossing remain unknown, preventing new biomimetic engineering strategies. To address the limitations of current therapeutics, I propose to identify and fuse subpopulations of EVs that efficiently cross the BBB and target OPCs, load them with microRNA-219, an OPC differentiating agent, to engineer a bioavailable and selective drug delivery vehicle. Building on results obtained in my preliminary data, I will carry out this project in three steps: (1) to optimize a method of fluorescence activated vesicle sorting to identify and isolate BBB-crossing EVs; (2) to elucidate the molecular mechanisms and key proteins during BBB transcytosis using a functional transwell model; and (3) to produce eEVs via fusion of endogenous EVs and loading with remyelinating therapeutics. We will quantify eEV ability to cross the BBB and target OPCs to initiate differentiation and produce myelin in vitro and in vivo. This project is focused on producing a novel therapeutic uniquely suited to PMS, but this pipeline to engineer EVs with multiple targeted functions could be applied to address drug delivery barriers for many medical problems. This project was developed in parallel with a rigorous training plan to enhance my training and technical skills in the areas of neurology, pharmacology, and translational medicine. This plan will enable my transition to independence as I focus on my long-term goal of pursuing an academic career developing neurological therapeutics. Training will exploit the university’s many resources for professional and educational development.


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 = -$16,344 )
2025	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/24/2025	NON-COMPETING CONTINUATION	-$4,584
2025	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/14/2024	NON-COMPETING CONTINUATION	-$11,760
														Subtotal = -$16,344

Issue Date FY: 2024 ( Subtotal = $41,378 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	5/9/2024	NON-COMPETING CONTINUATION	$1,280
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/24/2023	NON-COMPETING CONTINUATION	$40,098
														Subtotal = $41,378

Issue Date FY: 2023 ( Subtotal = $40,098 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/1/2022	NON-COMPETING CONTINUATION	$39,156
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	2/9/2023	NON-COMPETING CONTINUATION	$942
														Subtotal = $40,098

Issue Date FY: 2022 ( Subtotal = $39,156 )
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	11/19/2021	NEW	$0
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/19/2021	NEW	$38,440
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	1	5/20/2022	NEW	-$1
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	4/27/2022	NEW	$717
														Subtotal = $39,156

Grand Total All Awards = $104,288

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Engineered extracellular vesicles as a targeted drug delivery system for multiple sclerosis

Award Number: F31NS120590

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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