# Ultrasound Cavitation for Facilitated Cardiac Transduction of AAV

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $694,385

## Abstract

SUMMARY
There is intense interest in gene therapy for the treatment of a wide variety of inherited and acquired
cardiovascular diseases. Yet, progress in this field has been limited because of the low efficiency in transfection
for naked DNA vectors such as plasmids, and the adverse effects associated with more efficient viral vectors. A
promising solution to these problems has been the development of bioengineered adeno-associated virus (AAV)
vectors, which are members of the parvovirus family that are maintained as nuclear episomes. Despite the
success of AAVs in preclinical studies, early clinical trials indicate that the high doses of AAVs required for
therapeutically-sufficient myocyte transduction are associated with dose-related serious and sometimes fatal
immune reactions. This dose-related safety issue could be overcome by increasing the efficiency of
cardiomyocyte-specific AAV transduction. Our laboratories originally pioneered the use of ultrasound (US)
inertial cavitation of cationic microbubble (MB) vectors to augment delivery of plasmid DNA, which is confined
predominately to perivascular cells. More recently, our pilot experiments indicate that MB cavitation with US
within the diagnostic frequency and power range can markedly augment transduction of AAV9, which has
myocyte tropism, and that transduction occurs almost exclusively in cardiomyocytes. Importantly, enhanced
transduction of AAV does not require coupling of the vector to the MB surface. The overall goal of this proposal
is to better understand the mechanisms and ideal conditions for cavitation-facilitated AAV transduction (CFAT)
in preparation for translation into humans. In Aim 1, murine studies will be used to evaluate the dose-related
efficacy, safety, and mechanisms responsible for CFAT using recombinant AAV9 optical reporter systems. In
this Aim, we will also optimize the acoustic condition focusing on key US variables such as acoustic pressure,
pulse duration, and line density. Mechanisms for enhanced transduction with CFAT will be studied with a focus
on cell responses that occur with inertial cavitation of MBs that are likely to increase AAV transport from the
blood pool including glycocalyx modification, caveolin-mediated transcytosis, altered cell junction permeability,
and sialidasae activity. In Aim 2, we will perform proof-of-concept studies demonstrating enhanced therapeutic
effect and safety of CFAT compared to conventional AAV9 therapy in a murine cardiomyopathy model. For these
studies, we will use mice with a known human mutation in the myosin binding protein-C3 gene that produces a
haploinsufficiency model of cardiac hypertrophy and reduced systolic function. As a key translational step, in
Aim 3 we will evaluate efficacy and safety of CFAT in non-human primates using an AAV9 encoding a Na/I
symporter to allow spatial and temporal assessment of transduction efficiency with positron emission tomography
imaging and 18F-tetrafluoroborate. Completion of the...

## Key facts

- **NIH application ID:** 10779301
- **Project number:** 1R01HL171377-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Brent A French
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $694,385
- **Award type:** 1
- **Project period:** 2024-08-06 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10779301

## Citation

> US National Institutes of Health, RePORTER application 10779301, Ultrasound Cavitation for Facilitated Cardiac Transduction of AAV (1R01HL171377-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10779301. Licensed CC0.

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