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Structural and mechanistic insights into AAV Rep mediated site-specific integration and packaging

Award Number: R01GM124204
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2017
PERIOD OF PERFORMANCE END DATE: 08/30/2030

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Structural and mechanistic insights into AAV Rep mediated site-specific integration and packaging - PROJECT SUMMARY The Adeno-Associated Virus (AAV) is the leading vector in gene therapy, with several FDA and European Regulatory Commission-approved viral gene therapy products. However, various obstacles impede the widespread clinical use of AAV vectors. Key challenges include developing innovative methods to enhance the production of high-titer AAV preparations and creating new AAV vectors capable of incorporating larger DNA sequences. A thorough understanding of the AAV DNA packaging mechanism is essential to address these challenges, yet our knowledge of this process at a molecular level remains limited. In this project renewal, we will focus on the AAV packaging mechanism to achieve an atomic and mechanistic comprehension and apply our discoveries to optimize packaging efficiency. Aim 1: Molecular Characterization of Rep-ITR complexes and their function during DNA replication and packaging. Before packaging, the ssDNA genome needs to be generated and prepared for packaging. This process requires the completion of DNA replication through the terminal resolution reaction. We aim to characterize all the catalytic steps of this process reaction structurally. Aim 2: Structural and Biochemical Characterization of Rep40 Motor Activity: Towards Designing a Better Packaging Machine. The helicase activity of the small Reps (Rep52 and Rep40) is essential for packaging the AAV genome into the capsid. However, these proteins are monomeric in solution and form dimers transiently in the presence of ATP and ssDNA. Here, we will study the active quaternary structure of Rep40, catalog the motor activities of all AAV Rep serotypes and other parvoviral NS1 helicases to understand the structural determinants of motor activity. We hypothesize that generating a Rep40 protein with enhanced motor activity will result in a more efficient packaging machine. Aim 3: Structural and Biochemical Characterization of Rep-Capsid Interactions. We plan to employ a combination of biochemical, cell-based, and structural studies to gain insight into how the Rep packaging machinery interacts with the capsid. Furthermore, we will utilize native mass spectrometry to monitor these interactions. Our research will culminate in obtaining a Cryo-EM structure of the empty capsid bound to the Rep-ITR complex.


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 = $1,453,686 )
2026	2026	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	001	9	8/18/2026	COMPETING CONTINUATION	$1,455,161
2026	2026	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	002	9	9/21/2026	COMPETING CONTINUATION	$0
2026	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	8	5/20/2026	NON-COMPETING CONTINUATION	-$1,475
														Subtotal = $1,453,686

Issue Date FY: 2025 ( Subtotal = $326,025 )
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	8	11/21/2024	NON-COMPETING CONTINUATION	$293,423
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	001	8	8/8/2025	NON-COMPETING CONTINUATION	$32,602
														Subtotal = $326,025

Issue Date FY: 2024 ( Subtotal = $326,025 )
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	7	10/30/2023	NON-COMPETING CONTINUATION	$293,423
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	001	7	6/17/2024	NON-COMPETING CONTINUATION	$32,602
														Subtotal = $326,025

Issue Date FY: 2023 ( Subtotal = $341,854 )
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	001	6	11/3/2022	NON-COMPETING CONTINUATION	$307,668
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	002	6	2/16/2023	NON-COMPETING CONTINUATION	$34,186
2023	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	5	11/2/2022	COMPETING CONTINUATION	$0
														Subtotal = $341,854

Issue Date FY: 2022 ( Subtotal = $436,340 )
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	5	12/15/2021	COMPETING CONTINUATION	$343,889
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	002	5	3/6/2022	COMPETING CONTINUATION	$0
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	003	5	8/11/2022	SUPPLEMENT FOR EXPANSION	$92,451
2022	2020	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	001	4	3/6/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $436,340

Issue Date FY: 2020 ( Subtotal = $298,625 )
2020	2020	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	4	7/29/2020	NON-COMPETING CONTINUATION	$298,625
														Subtotal = $298,625

Issue Date FY: 2019 ( Subtotal = $385,645 )
2019	2019	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	3	7/30/2019	NON-COMPETING CONTINUATION	$298,801
2019	2019	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	001	3	8/6/2019	SUPPLEMENT FOR EXPANSION	$86,844
														Subtotal = $385,645

Issue Date FY: 2018 ( Subtotal = $298,547 )
2018	2018	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	2	7/17/2018	NON-COMPETING CONTINUATION	$298,547
														Subtotal = $298,547

Issue Date FY: 2017 ( Subtotal = $293,060 )
2017	2017	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Biomedical Research and Research Training	000	1	9/19/2017	NEW	$293,060
														Subtotal = $293,060

Grand Total All Awards = $4,159,807

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Structural and mechanistic insights into AAV Rep mediated site-specific integration and packaging

Award Number: R01GM124204

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2017

PERIOD OF PERFORMANCE END DATE: 08/30/2030

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