# Unraveling the immune response to factor VIII

> **NIH NIH U54** · EMORY UNIVERSITY · 2021 · $1,618,258

## Abstract

Overall Component
Project Summary/Abstract
Hemophilia A is the most common severe congenital bleeding disorder. It is caused by mutations in the F8 gene
on the X chromosome that lead to deficiency or complete absence of blood coagulation factor VIII (fVIII). Current
management of patients with hemophilia is intravenous infusion of either plasma-derived or recombinant fVIII to
prevent bleeding or to treat bleeding after it has occurred. The most significant complication in the management
of patients with hemophilia A is the development of inhibitory antibodies (inhibitors) to fVIII. The future standard-
of-care of hemophilia A will be gene therapy. In preclinical gene therapy studies, the development of inhibitors
has prevented long-term correction of the genetic lesion.
We propose to create an Emory Factor VIII Center consisting of a group of highly interactive investigators with
diverse research skills and an established interest in the immunogenicity of fVIII. The central hypothesis is that
structural determinants in fVIII structure, including its glycans, are responsible for its highly immunogenic
behavior. The three projects in this proposal address these themes with aims to determine the relationship of
fVIII structure, fVIII glycobiology and fVIII in gene therapy settings to its immunogenicity. In Project 1, “The
Structural Basis for Immune Recognition of Factor VIII”, we seek to identify immunogenic structures that can be
modified to produce a less immunogenic fVIII molecule. This will be accomplished by using X-ray crystallography,
hydrogen-deuterium exchange mass spectrometry, single-particle negative-stain electron microscopy, surface
plasmon resonance spectroscopy and analytical ultracentrifugation to determine the structure of fVIII and fVIII
immune complexes. In Project 2, “The Immunobiology of Factor VIII”, the role of fVIII glycans and the impact of
microbiota on anti-αGal antibody development on inhibitor formation will be determined. Additionally, the
immunogenicity of fVIII immune complexes characterized in Project 1 will be evaluated. In Project 3, “Novel
Factor VIII Technologies for the Prevention or Treatment of Factor VIII Inhibitors”, the molecular composition
and immune reactivity of bioengineered recombinant infusion products as well as liver-directed AAV and HSC-
directed LV gene therapy derived fVIII will be analyzed. Critical design parameters associated with
immunogenicity and inhibitor eradiation potential of liver-directed AAV-fVIII gene therapy will be identified.
Additionally, the immunogenicity and inhibitor eradicating potential of non-genotoxic HSC-directed LV gene
therapy protocols will be evaluated. This program is highly significant because it addresses causal mechanisms
for fVIII inhibition and implications for modifying these mechanisms to improve therapy for hemophilia A patients.

## Key facts

- **NIH application ID:** 10147141
- **Project number:** 5U54HL141981-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** John S. Lollar
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,618,258
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10147141

## Citation

> US National Institutes of Health, RePORTER application 10147141, Unraveling the immune response to factor VIII (5U54HL141981-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10147141. Licensed CC0.

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