# Molecular Interactions of FVIII and VWF

> **NIH NIH R01** · VERSITI BLOOD HEALTH, INC. · 2020 · $586,287

## Abstract

PROJECT SUMMARY
Hemophilia A (factor VIII deficiency) and von Willebrand disease (VWF deficiency) are well recognized severe
and/or common bleeding disorders that require frequent treatment with IV infusion of clotting factors – FVIII
and VWF respectively. Studies by our laboratory and others suggest a unique relationship between VWF and
FVIII that will be explored further in this proposal. While prophylaxis to prevent bleeding is the current standard
of care, this requires infusions several times a week. While gene therapy could be curative, studies in patients
have yet to achieve adequate efficacy except in patients with hemophilia B (factor IX deficiency). Over the
past several years our laboratory has focused on delivering FVIII by targeting expression to the platelet so that
FVIII is stored together with VWF and this approach results in therapeutic efficacy even in the presence of high
titer FVIII inhibitors. The local release of the FVIII/VWF complex circumvents the immediate inactivation of
FVIII and permits cessation of bleeding even in the face of high-titer FVIII inhibitory antibodies. In Aim-1 a
second animal model has been developed to study the role of the VWF and FVIII complex in gene therapy of
hemophilia A even in the context of FVIII inhibitors in a rat model that has both spontaneous bleeding, a high
propensity to form FVIII inhibitory antibodies, and has a blood volume size that enables easy sequential
sampling unlike the mouse where sequential time points require animal sacrifice rather than sequential
phlebotomy. This can substantiate the efficacy of 2bF8 in an inhibitor prone model and potentially demonstrate
efficacy in preventing spontaneous bleeding – a characteristic that cannot be studied in the mouse or the dog
were spontaneous bleeding is difficult to study. While it is well recognized that VWF prolongs the survival of
FVIII, in Aim 2 we will explore the functional importance of this VWF delivering FVIII to the site of the evolving
thrombus. In Aim 3 we will further study VWF and FVIII synthesis and the cells that produce them as a
complex and as individual proteins. These three aims will further our understanding of the biologic role for the
complex of FVIII and VWF in normal hemostasis and thrombosis and through these interactions offer a
strategy for effectively treating hemophilia A subjects with FVIII inhibitors through a unique gene therapy
strategy that ectopically expresses FVIII with VWF in platelets.

## Key facts

- **NIH application ID:** 9851917
- **Project number:** 5R01HL139847-03
- **Recipient organization:** VERSITI BLOOD HEALTH, INC.
- **Principal Investigator:** ROBERT R MONTGOMERY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $586,287
- **Award type:** 5
- **Project period:** 2018-02-15 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851917

## Citation

> US National Institutes of Health, RePORTER application 9851917, Molecular Interactions of FVIII and VWF (5R01HL139847-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9851917. Licensed CC0.

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