# Immunology of factor IX gene transfer to liver

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $393,750

## Abstract

ABSTRACT
Adeno-associated viral (AAV) vectors are in advanced clinical development for treatment of multiple genetic
diseases. Nevertheless, unexpected immune responses have substantially slowed down clinical advances, as
for instance in the case of the X-linked bleeding disorder hemophilia, where activation of CD8+ T cells
continues to cause complications for patients. For example, CD8+ T cells directed against AAV capsid target
transduced human hepatocytes thus causing liver toxicity and loss of expression. Similarly, upon gene transfer
into skeletal muscle aimed at treating a variety of genetic diseases, CD8+ T cell responses directed against
capsid, and in some patients against the transgene product, were observed. These were often associated with
prolonged inflammation and resulted in cytotoxicity and/or cytokine production and partial loss of expression.
Another major concern for many replacement therapies is antibody formation against the transgene product,
which we have extensively addressed in previous funding cycles. Our key discovery that hepatic AAV gene
transfer can induce immune tolerance to the transgene product (partly through induction of regulatory T cell,
Treg) facilitated the establishment of effective clinical gene therapies for hemophilia, as well as the pre-clinical
development of immune modulatory gene therapies for multiple diseases. We have since established several
alternative methods to prevent or reverse antibody formation against therapeutic proteins. Because of the
clinical observations summarized above, we are now performing in-depth studies on the mechanism of CD8+ T
cell activation in AAV gene transfer. We have also identified novel approaches to prevent such responses by
blocking require innate immune signals. To address major gaps in knowledge on CD8+ T cell activation in
response to AAV and to reduce immunogenicity of AAV gene transfer, we propose to define the mechanism of
dendritic cell licensing in AAV gene transfer; to define the mechanisms that lead to transgene product-specific
CD8+ T cell responses; and to develop innate immune blockade to prevent CD8+ T cell activation upon AAV-
FIX gene transfer.

## Key facts

- **NIH application ID:** 10310465
- **Project number:** 5R01AI051390-22
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Roland W. Herzog
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $393,750
- **Award type:** 5
- **Project period:** 2002-04-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10310465

## Citation

> US National Institutes of Health, RePORTER application 10310465, Immunology of factor IX gene transfer to liver (5R01AI051390-22). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/10310465. Licensed CC0.

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