# AAV capsids and their cellular interactions

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $410,830

## Abstract

The Adeno-associated viruses (AAVs) are ssDNA packaging viruses belonging to the Dependoparvovirus genus
of the Parvoviridae. Gene delivery systems based on the AAVs recently entered an exciting phase with the FDA
approval of Luxturna, an AAV serotype 2 (AAV2)-based gene therapy for treating a monogenetic defect in the
eye. However, the success of Luxturna was ushered by the fact that the eye is an immune privileged organ and
direct administration avoids pre-existing host immunity. This remains a significant challenge to the therapeutic
efficacy of the AAV gene delivery system. More recently, members of the Bocaparvovirus genus of the
Parvoviridae have also been developed as viral gene delivery vectors, also for treating monogenetic diseases.
However, high level of seroprevalence of host antibodies against AAVs and bocaviruses (BoVs), at ≥70%,
represents a major challenge to full therapeutic realization of both systems. The primary focus of this project has
been to characterize the antigenic structures of primate AAVs, using mouse monoclonal antibodies (Mabs), as
they relate to capsid determinants of receptor attachment, tissue tropism, and transduction efficiency (gene
expression). We pioneered the use of this information for molecular engineering of AAV vectors able to escape
antibody recognition and currently under evaluation as potential clinical vectors. However, there is need to
confirm that the “polyclonal” information obtained by mapping several mouse Mabs for each AAV serotype
studied recapitulates the polyclonal human response. In this renewal application, we will characterize the ability
of human and non-human primate (NHP) sera to neutralize or bind and not neutralize vector transduction. This
will guide the engineering of antibody escape and/or transduction efficacy and thus therapeutic utility. We expand
our viral models to include non-primate AAVs and BoV vectors in an effort to expand the pool of parvoviral
vectors available for use. Our three specific aims will ask four new questions: (1) “Do primate antibodies share
epitopes with the previously described murine Mabs?” (2) “Do the binding sites of neutralizing and non-
neutralizing binding antibodies overlap”? (3) “Do non-primate AAVs naturally escape pre-existing neutralizing
primate antibodies and capable of transducing human cells?” And (4) “Can we engineer the antigenic sites on
BoV vectors to evade neutralization by antibodies while retaining or improving the parental transduction
efficiency?”. We will use cryo-electron microscopy and image reconstruction to determine high-resolution
structures of non-primate AAVs and BoV capsids, alone and in complex with glycan receptors, to ≤3 Å resolution
and the structures of AAV/BoV capsid – human/NHP antibodies to between 3 to 4 Å resolution. This is routine
in our group. We will use the information obtained to engineer vectors that retain their cell binding properties but
evade recognition by human/NHP. We will evaluate these vectors...

## Key facts

- **NIH application ID:** 9896537
- **Project number:** 2R01GM082946-10
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Mavis Agbandje-Mckenna
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $410,830
- **Award type:** 2
- **Project period:** 2007-09-17 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896537

## Citation

> US National Institutes of Health, RePORTER application 9896537, AAV capsids and their cellular interactions (2R01GM082946-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9896537. Licensed CC0.

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