Structural and mechanistic understanding of antibody inhibition of AAV2 gene therapy
Active Project Grant Awarded Last action
- Award ID
- F31AI191797
- Recipient
-
University Of Florida UEI NNFQH1JAPEP3
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $94,052
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 4% complete
- Originally
- Place of performance
- Gainesville, FL 32611, USA
Award details come from USAspending.gov.
Description
- 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.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Amendment | $576 | |
| Amendment | $46,738 | |
| Original award | $46,738 |
Quick answers
Who received award F31AI191797?
F31AI191797 was awarded to University Of Florida by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on October 1, 2026.
How much is award F31AI191797 worth?
$94,052 has been obligated on F31AI191797.
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