# Rapid Transient Depletion of Pre-existing Antibodies for rAAV Gene Delivery

> **NIH NIH R21** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $194,375

## Abstract

Project Summary:
This proposal targets a critical challenge in the translation of AAV-mediated gene therapy, the widespread
pre-existing αAAV antibodies (Abs) in humans. Pre-existing αAAV-Abs block AAV vectors from entering and
transducing target cells. Currently, only αAAV-Abs-negative individuals are eligible for AAV-gene therapy
treatment, because no effective approach is available to overcome this challenge. Our recently published
studies demonstrated that broad immune targeting is required for effective Ab-depletion by immune
suppression (IS) and identified an effective IS Ab-depletion approach in a mouse model, using combination
of rapamycin and prednisolone. However, this IS regimen requires up to 8-12-week-long daily administration.
The IgG degrading enzymes of Streptococci (IdeS) are cysteine proteases that specifically cleaves IgG
molecules. Numerous studies have demonstrated rapid and effective IgG degradation by IdeS in animals and
in humans, supporting the therapeutic potential of IdeS. IdeS has a short half-life of 4.9±2.8hr with no
demonstrated dose limiting toxicity. We therefore hypothesize that IV IdeS administration may offer a novel
tool to overcome the pre-existing αAAV-IgG for rAAV-mediated gene therapy. This proposal is to develop a
novel effective ab-depletion approach for the effective translation of rAAV gene therapy to treat diseases in
clinic, using a mouse model of MPS IIIB, a devastating neuropathic lysosomal storage disease, for which not
treatment is currently available. Taking advantage of demonstrated rapid effective Ab removal by IdeS, this
proposal will lead to the development of a novel approach for effective depletion of pre-existing αAAV-Abs,
which may make all patients in need eligible to AAV gene therapy, and viral gene therapy in general. We
therefore believe that IdeS may offer the answer to the challenge posed by pre-existing Abs to the translation
of gene therapy products using AAV and other viral vectors.

## Key facts

- **NIH application ID:** 9950992
- **Project number:** 5R21AI146653-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** HAIYAN FU
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $194,375
- **Award type:** 5
- **Project period:** 2019-06-12 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9950992

## Citation

> US National Institutes of Health, RePORTER application 9950992, Rapid Transient Depletion of Pre-existing Antibodies for rAAV Gene Delivery (5R21AI146653-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9950992. Licensed CC0.

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