# Center for the Investigation of Factor VIII Inhibitors and Glycosylation

> **NIH NIH U54** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $1,404,536

## Abstract

PROJECT SUMMARY
A major obstacle in treating hemophilia A is that ~25% of patients develop high-titer, neutralizing anti-factor VIII
(FVIII) antibodies (inhibitors) following protein replacement therapy. It is also anticipated that this problem will
occur following gene therapy in at least a subset of patients. It is particularly challenging to treat hemophilia
patients who have developed inhibitory antibodies. Bypassing therapies that are used to treat these patients
sometimes have limited efficacy and are very costly. The anti-FVIII inhibitory antibody formation results from a
complex multifaceted immune response involving both genetic and environmental risk factors. Several “danger
signals” have been demonstrated to be associated with risks of inhibitor formation. However, the potential
triggers to activate anti-FVIII responses are not fully understood. For example, patients with identical mutations
in FVIII gene can have differential risks in inhibitor development following protein replacement therapy. Moreover,
there were some implications that different FVIII products may exhibit different degrees of inhibitor risks. In recent
years, it has been demonstrated that glycans are crucial for the immune system, as some of the most important
interactions between the immune system and viruses or bacteria or exogenously added proteins are mediated
by protein-glycan interactions. Glycosylation is involved in almost every step of the immune activation pathway.
Glycans are a key in the recognition of non-self events and an altered glycome can lead to activation of immune
responses. Glycosylation is also involved in the cellular mechanisms that control the threshold of TCR activation,
immune cell trafficking, TCR and BCR signaling, antibody function, and more. We hypothesize that the impact
of glycans in the induction of immune response or tolerance to FVIII can be two-fold: one is that the interaction
of glycosylated FVIII antigens and host immune system with specific glycan profiles can be significant in
determining the risk of inducing anti-FVIII immune response; and the second is that the recognition of and ensued
immune activation by exogenously added protein or gene expression can be altered by different extent or
patterns of FVIII glycomes. Therefore, in order to more fully understand the spectrum of potential glycosylation
influence on the development of anti-FVIII inhibitor responses, we propose to first look into the influence of host
glycan profiles in the development of anti-FVIII response both in humans and mice with different backgrounds.
Next we will characterize the immune responses elicited by delivery of FVIII molecules with different extent or
patterns of glycosylation and investigate the mechanism of immune activation. From this study, we wish to define
specific immunologic trigger by glycosylation and its associated mechanisms, leading to prevention or elimination
of FVIII inhibitors.

## Key facts

- **NIH application ID:** 9930446
- **Project number:** 7U54HL142019-03
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Lei Li
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,404,536
- **Award type:** 7
- **Project period:** 2018-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930446

## Citation

> US National Institutes of Health, RePORTER application 9930446, Center for the Investigation of Factor VIII Inhibitors and Glycosylation (7U54HL142019-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9930446. Licensed CC0.

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