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Cell-specific nanocarrier with endocytic and endosomolytic activities for therapeutic genome editing

Award Number: UG3TR002866
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract( ! Our goal is to develop novel nanoplatforms for efficient in vivo delivery of genome editing machinery into specific cell types and tissues; nanodelivery systems that are non-toxic and can be used for therapeutic genome editing in human. Regarding nanocarrier, we will engineer the innovative hepatitis E viral nanoparticle (HEVNP) developed by the Cheng (one of the PIs) laboratory, such that cell specific targeting/endocytic ligand will be displayed on the viral nanoparticle surface, and genome editing machinery and endosomolytic peptides will be encapsulated inside the core. HEVNP is resistant to gastric acid environment and therefore can deliver payload to intestine via oral route. We hypothesize that through introduction of stealth peptide elements and cell-type specific targeting ligand on the viral capsid proteins, such novel nanocarrier can deliver gene editing machinery to specific cell type, not only via the oral route, but also via the intravenous route. Our goal is to genome edit intestinal adenomatous polyp cells, intestinal epithelial cells, and intestinal stem cells of ApcMin/+ mice (a mouse model of familial adenomatous polyposis) by correcting a mutant Apc tumor suppressor gene, leading to prevention of new polyp formation and regression of existing polyps (size & number). We will employ the enabling one-bead one-compound (OBOC) and one-bead two-compound (OB2C) combinatorial library methods (invented by Dr. Lam, one of the PIs) to develop D-amino acid containing targeting/endocytic ligands against intestinal adenomatous polyp cells, intestinal epithelial cells, and intestinal stem cells of ApcMin/+ mice. We will use the OBOC method to discover membrane active peptides with endosomolytic activities. These endosomolytic peptides will bind to endosome at pH5 but not to plasma membrane at pH7.2. Specific aims are as follows: UG3 (Phase 1) Aim 1: To design and synthesize OB2C/OBOC combinatorial libraries for the discovery of (a) cell- specific targeting and endocytic peptides, and (b) endosomolytic peptides. Aim 2: (a) To engineer hepatitis E viral nanoparticle (HEVNP) with cell-specific targeting ligands, (b) to design genome editing machinery for GFP, luciferase and Apc correction, and (c) to assemble a series of nanoconstructs encapsulating the genome machinery and endosomolytic peptides. Aim 3: To evaluate the genome editing functions of the nanoconstructs from aim 2, in vitro with murine intestinal enterocytes and adenomatous polyp cells, and in vivo (oral & iv) with Apcmin/+ mice. UH3 (Phase 2) Aim 1, 2 & 3: To scale up the production of the genome editing nanodelivery platform. To perform preclinical pharmacology/toxicology studies in mouse and Rhesus macaques. To collaborate with investigator from SCGE Large Animal Testing Centers on validation of the delivery system. !


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: 2023 ( Subtotal = -$1,265 )
2023	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Trans-NIH Research Support	000	3	9/26/2023	NON-COMPETING CONTINUATION	-$1,265
														Subtotal = -$1,265

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Trans-NIH Research Support	000	3	9/13/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $784,845 )
2021	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Trans-NIH Research Support	001	3	9/8/2021	NON-COMPETING CONTINUATION	$784,845
2021	2020	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Trans-NIH Research Support	000	2	1/7/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $784,845

Issue Date FY: 2020 ( Subtotal = $765,041 )
2020	2020	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Trans-NIH Research Support	001	2	8/1/2020	NON-COMPETING CONTINUATION	$765,041
2020	2019	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Trans-NIH Research Support	000	1	3/1/2020	NEW	$0
														Subtotal = $765,041

Issue Date FY: 2019 ( Subtotal = $736,158 )
2019	2019	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Trans-NIH Research Support	000	1	8/22/2019	NEW	$736,158
														Subtotal = $736,158

Grand Total All Awards = $2,284,779

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Cell-specific nanocarrier with endocytic and endosomolytic activities for therapeutic genome editing

Award Number: UG3TR002866

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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