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Structural and Mechanistic Understanding of Antibody Inhibition of AAV2 Gene Therapy

Award Number: F31AI191797
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/16/2026
PERIOD OF PERFORMANCE END DATE: 05/15/2028

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Structural and Mechanistic Understanding of Antibody Inhibition of AAV2 Gene Therapy - Project Summary/Abstract Adeno associated viruses (AAVs) are premier viral vectors for gene therapy. AAV vectors consists of the capsid of an AAV packaging a transgene intended to treat a particular genetic disorder. A major obstacle to AAV mediated gene therapy is pre-existing neutralizing antibodies (NAbs) to the AAV serotype employed. AAVs are non-pathogenic, however they are endemic in the population and seropositivity for anti-AAV antibodies ranges from 20%-80% depending on the serotype. Prior to treatment patients must be screened for pre-existing NAbs, patients that fail to meet inclusion criteria are unable to receive treatment. Furthermore, the mechanism by which many of these NAbs inhibit viral transduction is not fully understood. Overcoming the barrier to treatment presented by NAbs is of utmost importance to develop the use of AAVs as gene therapy vectors. The McKenna lab has demonstrated that NAbs can be evaded by structure-guided rational design of the AAV capsid surface. Additionally, it has been shown that mouse derived NAbs favor interacting with different regions of the capsid surface than human derived NAbs, thus highlighting the importance of using human derived NAbs for structure-guided capsid engineering. The project proposed for this fellowship aims to employ structure-guided rational design of a recombinant AAV2 antibody escape variant by investigating the key contact residues between wild-type AAV2 and a cohort of 31 human NAbs derived from a naturally occurring AAV2 infection in pediatric hepatitis patients (Aim 1). Additionally, the mechanism by which these NAbs inhibit viral transduction will be investigated by in vitro cell binding and trafficking assays (Aim 2). To the best of our knowledge, this is the first time such a study has been conducted using NAbs derived from a naturally occurring AAV2 infection in humans. Production of a novel AAV2 antibody escape variant will increase the cohort of treatable patient s and allow for redosing in the future, thereby reducing patient burden. Elucidation of the NAb mechanism will serve to guide vector and treatment design reducing costs and increasing patient safety. Furthermore, the research entailed in this project will greatly aid my training to become and independent scientist and the environment at University of Florida will ensure my successful training.


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 = $47,314 )
2026	2026	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	1	5/1/2026	NEW	$576
2026	2026	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	002	1	5/1/2026	NEW	$0
2026	2026	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	1	4/1/2026	NEW	$46,738
														Subtotal = $47,314

Grand Total All Awards = $47,314

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Structural and Mechanistic Understanding of Antibody Inhibition of AAV2 Gene Therapy

Award Number: F31AI191797

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/16/2026

PERIOD OF PERFORMANCE END DATE: 05/15/2028

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