# Oral Tolerance for Hemophilia

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $746,710

## Abstract

PROJECT SUMMARY/ABSTRACT.
The current standard of care for the X-linked bleeding disorder hemophilia is intravenous (IV) infusion of
recombinant factor VIII (FVIII, for hemophilia A) or factor IX (FIX for hemophilia B). These protein products
are expensive, require frequent repeated IV injections (which is painful and inconvenient), and are often
targeted by antibody (“inhibitor”) responses; thereby complicating/neutralizing therapy, creating
immunotoxicities, and further increasing costs. In fact, inhibitor formation, an antigen-specific CD4+ T helper
cell-driven B cell response, is widely considered the most serious complication of current therapy for
hemophilia. Forming an interdisciplinary research team to address this problem, our laboratories have been
closely collaborating since 2007 to develop a bioengineering-based approach. We conceived and now validated
the concept that oral delivery of bioencapsulated FVIII and FIX antigens produced by the chloroplasts of
transgenic plants could suppress inhibitor formation in animal models of hemophilia. FVIII and FIX antigens
were effectively delivered to the epithelium of the small intestine when expressed as fusions to a transmucosal
carrier, and subsequently taken up by dendritic cells (DCs) in the lamina propria (LP) and Peyer's patches (PP).
Tolerance was established (over a wide range, including very low antigen doses) by induction of multiple
subsets of regulatory T cells (Treg) in an IL-10 dependent manner. In addition, this approach prevented and
also reversed anaphylaxis against FIX. Importantly, we were able to generate chloroplast transgenic edible crop
plants (lettuce), and scale up of production was successful to a commercial system that is used to cost-
effectively generate GMP material. To further advance this approach, we propose the following specific aims: 1.
Generate the next generation of transplastomic edible crop plants expressing FVIII antigen using cutting-edge
chloroplast genomics tools and alternative transmucosal carriers. 2. Continue to define the mechanism of oral
tolerance induction/immune regulation, in part through use of a model antigen. 3. Identify optimal plants for
oral tolerance induction in hemophilia A mice; perform translational studies in hemophilia A dogs; and further
strengthen oral tolerance by enhancing immune regulation or manipulating T cell metabolism. This work will
facilitate translation of oral tolerance for hemophilia into clinical trials, define the mechanism of how plant
cell-based oral tolerance is accomplished, pave the way for future combination protocols for optimal oral
tolerance induction, and further advance genetic engineering of plants for biomedical applications.

## Key facts

- **NIH application ID:** 9840502
- **Project number:** 5R01HL133191-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** HENRY DANIELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $746,710
- **Award type:** 5
- **Project period:** 2017-04-10 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840502

## Citation

> US National Institutes of Health, RePORTER application 9840502, Oral Tolerance for Hemophilia (5R01HL133191-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840502. Licensed CC0.

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