# Enhancing immune regulation in gene therapy for hemophilia

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $729,657

## Abstract

PROJECT SUMMARY/ABSTRACT
Adeno-associated viral (AAV) vectors are widely used in human gene therapy: e.g. two products have been FDA
approved and three vectors, which correct the X-linked bleeding disorder hemophilia by hepatic gene transfer,
are in Phase III clinical trials. Undesired and sometimes unexpected immune responses to vector or transgene
product can impede long-lasting therapy, including CD8+ T cell and antibody responses to transgene product
and viral capsid, which at high systemic vector doses occasionally induce severe immune toxicities.
Consequently, short-term immune suppression, for example by corticosteroids has now been incorporated into
many protocols and B cell depletion is being explored. This proposal seeks to elucidate the molecular and cellular
underpinnings of innate and adaptive immune responses to AAV-transduced mouse and human hepatocytes.
The experiments are designed to test the central hypothesis that a targeted blockade of innate immune
responses and specific cytokine signaling pathways combined with an empowered immune regulation are
requisite for a successful hepatic AAV-directed gene transfer. This concept is based upon the outcomes of
studies, which establish that: 1. The liver is an excellent target for immune tolerance induction to transgene
products owing to its microenvironment that ultimately empowers regulatory T cells (Treg) to control antibody
and T cell responses. 2. Immune modulatory protocols using rapamycin by itself or in combination with other
drugs result in the desired immune regulation. 3. Cross-priming of capsid-specific CD8+ T cells requires
cooperation between different subsets of dendritic cells, which critically involves TLR9-MyD88 signaling and IFN
I. 4. For TLR9-independent activation of transgene product-specific CD8+ T cells in the liver, IL-1R is requisite.
5. State-of-the art in vitro culture techniques and ability to in vivo expand both human hepatocytes and human
innate immune cells in immunodeficient mice have been developed. 6. Formation of neutralizing antibodies
directed against coagulation factor VIII and capsid upon hepatic AAV gene transfer can be prevented and
sustained therapy is achieved hemophilia A mice by optimal immune modulation. Based on these findings, the
proposal seeks to i) define the innate immune response of human hepatocytes and liver environment in AAV
gene transfer; ii) define the mechanism by which the IL-1R-MyD88 signaling pathway promotes CD8+ T cell
responses in hepatic AAV gene transfer; and iii) develop optimal transient immune modulatory regimens that
prevent B and T cell responses to the transgene product and the vector and thereby assure sustained therapy.

## Key facts

- **NIH application ID:** 10401846
- **Project number:** 5R01HL131093-06
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Ype Peter De Jong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $729,657
- **Award type:** 5
- **Project period:** 2016-07-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401846

## Citation

> US National Institutes of Health, RePORTER application 10401846, Enhancing immune regulation in gene therapy for hemophilia (5R01HL131093-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10401846. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*