# AAV capsids and their cellular interactions

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2024 · $419,859

## Abstract

Adeno-associated virus (AAV) vectors have become the leading biologic for the long-term
correction of monogenic diseases. Success in numerous clinical trials led in the approval of
currently six AAV-based biologics. However, significant challenges for their wide-spread
utilization remain including pre-existing immunities in large portions of the human population and
toxicities at high doses. Neutralizing antibodies originate from prior exposure to naturally
circulating AAVs that primarily target the capsid leading to vector inactivation and loss of treatment
efficacy. Patients having these antibodies are usually excluded from receiving these therapeutics.
Additionally, other aspects of the immune system pose significant barriers for effective gene
delivery especially following high dose AAV vector administration. These high doses are required
to counteract the low transduction efficiencies of many natural AAV variants to achieve sufficient
transgene expression for therapeutic success. The ability of AAV vectors to deliver their payload
to the target cells is determined by a series of interactions of the capsid to the cell surface
receptors as well as intracellular trafficking factors. Hence, the overall objective of this project is
to characterize these AAV capsids interactions structurally and functionally. Specific questions
our proposal will address are: “How do mAbs from clinical trial participants or donors with natural
AAV exposure bind and neutralize AAV capsids compared to the previously described mouse
mAbs?” (Aim 1) and “How do proteins of the innate immune system, receptors, and other
intracellular factors interact to the AAV capsids?” (Aim 2). We will use cryo-electron microscopy
to determine high-resolution structures of the complexes to ≤3 Å resolution and apply the obtained
information to engineer vectors that retain their cell binding properties but evade recognition by
human antibodies or defensins. Additionally, we will characterize non-primate AAVs and evaluate
their potential as gene delivery vectors (Aim 3). Due to highly diverse capsid amino acid sequence
compared to the commonly utilized AAV serotypes most pre-existing antibodies will be prevented
from binding. Thus, this aim will ask the question: “Can we design new AAV capsids utilizing
structural information from non-primate AAV, while retaining/inserting known receptor-binding
interfaces of the primate AAVs on the capsid surfaces to allow for transduction of human cells
and prevention of antibody neutralization and/or complement activation?” Overall, this project will
culminate in an expanded “pillbox” of engineered vectors with the ability to overcome the
challenges of the host immune responses and efficient gene transfer thereby improving clinical
efficacy and increase the cohort of patients eligible for treatment.

## Key facts

- **NIH application ID:** 10801515
- **Project number:** 2R01GM082946-14
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** ROBERT MCKENNA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $419,859
- **Award type:** 2
- **Project period:** 2007-09-17 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801515

## Citation

> US National Institutes of Health, RePORTER application 10801515, AAV capsids and their cellular interactions (2R01GM082946-14). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10801515. Licensed CC0.

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