# AAV-Exosomes: Escaping Neutralizing Antibody and Enhancing Delivery

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $796,394

## Abstract

SUMMARY
Gene therapy is a promising approach for the treatment of various monogenic diseases including inherited
cardiomyopathies and other types of heart failure. Adeno-associated vectors (AAV) are vectors of choice for
delivering genes to cardiomyocytes for long term expression and due to their safety in clinics. However, a
significant challenge to their successful use is futility caused by pre-existing antibodies (NAbs) as well as
subsequent development of immunity following AAV administration. NAbs prevent AAVs from infecting
target cells, greatly reducing transduction efficiency, and thus, clinical efficacy. Therefore, to advance gene
therapies for cardiovascular treatment for a wider population, it is essential to develop strategies to
circumvent NAbs.
Exosomes are extracellularly secreted nano-vesicles that shuttle selective biomolecules between neighboring
and distant cells. Recent studies have shown that exosomes can carry several types viruses and shield them
from antibody neutralization. Delivery of AAVs protected by carrier exosomes is a promising approach to
circumvent NAb neutralization in AAV-based gene therapy. Our in vitro and in vivo preliminary data suggest
that AAV-encapsulating exosomes (AAVExo) are 1) more resistant to NAb neutralization as compared to free
AAVs, 2) more efficient in delivering genes to the myocardium, 3) preserves viral cardiotropism, and 4) retains
the therapeutic benefits of AAV-mediated gene delivery.
Here, we aim to investigate the ability of AAVExo to evade NAbs and serve as a highly efficient gene
delivery tool for cardiovascular therapeutics. We have developed a method to isolate highly pure AAVExo
with minimum contamination from free-AAVs. Our central hypothesis is that AAVExo shields AAVs to
evade NAb and enhance gene delivery to the myocardium compared to free AAVs. Our major goal is
to develop a comprehensive understanding of the molecular mechanisms of NAb neutralization by AAVExo,
and 2) to determine the beneficial effects of therapeutic genes delivered by AAVExo in preclinical animal
models of heart failure. The specific aims are: AIM 1: Characterize AAVExo and determine its gene delivery
efficacy and molecular mechanisms of NAb evasion in vitro. AIM 2: Determine the gene delivery efficacy,
cardiotropism and mechanisms of NAb evasion of AAVExo in vivo. AIM 3: Optimize AAVExo purification
using a NanoDLD microfluidic device and determine the beneficial effect of AAVExo-SERCA2a in small and
large animal models of heart failure with preexisting NAb.

## Key facts

- **NIH application ID:** 10428364
- **Project number:** 5R01HL148786-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Susmita Sahoo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $796,394
- **Award type:** 5
- **Project period:** 2019-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428364

## Citation

> US National Institutes of Health, RePORTER application 10428364, AAV-Exosomes: Escaping Neutralizing Antibody and Enhancing Delivery (5R01HL148786-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10428364. Licensed CC0.

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