# A Phase I Clinical Trial Testing Feasibility of Hematopoietic Stem Cell Gene Therapy Using Platelet Factor VIII to Safely Improve Hemostasis for Severe Hemophilia A with Inhibitory Antibodies

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $1,589,707

## Abstract

PROJECT SUMMARY/ABSTRACT
 Patients with severe hemophilia A (PWHA) have a significant deficiency (<1% normal) in coagulation factor
VIII (FVIII) that frequently causes recurrent spontaneous bleeding episodes leading to significant morbidity and
mortality. Conventional therapy for HA employing the infusion of donor plasma FVIII cryoprecipitate product
can be complicated by blood-borne transmission of viral illnesses (including HIV & hepatitis C). Use of
recombinant FVIII (rFVIII) products has largely replaced the use of human-derived FVIII (because rFVIII
prevents risk of viral transmission); however, plasma FVIII remains a valuable resource for HA throughout the
world. Prophylactic therapy with FVIII requires the intravenous administration of FVIII 2-3 times weekly
throughout a patient's lifetime. Unfortunately, recurrent intravenous access, low compliance, break-through
bleeding, and joint-damage can occur despite FVIII prophylaxis. Additionally, ≈30% of HA develop
allo-antibodies to FVIII replacement products that inhibit its ability to restore hemostasis. Thus, treatment of
bleeding in these patients involves the administration of a costly “bypass” agent therapy (i.e., FVIII with
immune suppression and/or FVIIa). Success has been achieved by inducing immune tolerization to FVIII in
≈60% of HA with inhibitory antibodies by several rigorous infusions of FVIII (often in the setting of prophylaxis
with bypassing agents) although treatment for FVIII inhibitors remains a critical issue for HA patients.
 Due to its monogenic nature, HA is an ideal candidate for gene replacement therapy with the potential for
correction of HA. Promising approaches include the targeted expression of human FVIII to the liver by
intravenous infusion of naked DNA, the generation of a novel adeno-associated viral (AAV) vector equipped
with less immunogenic coat proteins, and vectors incorporating small active forms of FVIII (that conform to the
4.4 kb packaging capacity of AAV). However, these strategies exclude individuals with 1) inhibitory antibodies
to FVIII (≈30% PWHA), 2) pre-existing antibodies to the AAV (≈40% humans) and 3) chronic liver damage.
To address this problem of considerable clinical significance, we propose a first-in-human phase I clinical trial
employing a hematopoietic stem cell (HSC) gene therapy strategy that utilizes a lentiviral gene transfer vector
encoding human FVIII under the transcriptional control of the megakaryocyte-specific ITGA2B gene promoter
that targets expression of the FVIII gene in megakaryocytes causing ectopic synthesis, storage and
regulated-release of factor VIII from α-granules of activated platelets precisely at the site of vascular injury.
This proposal is supported by pre-clinical studies that showed platelet FVIII safely and efficiently improved
hemostasis in murine and canine models of HA without the development of inhibitory antibodies to FVIII and
even in the presence of pre-existing inhibitory antibodies to FVIII in m...

## Key facts

- **NIH application ID:** 10388261
- **Project number:** 5R01HL142791-04
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** MARY EAPEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,589,707
- **Award type:** 5
- **Project period:** 2019-04-05 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10388261

## Citation

> US National Institutes of Health, RePORTER application 10388261, A Phase I Clinical Trial Testing Feasibility of Hematopoietic Stem Cell Gene Therapy Using Platelet Factor VIII to Safely Improve Hemostasis for Severe Hemophilia A with Inhibitory Antibodies (5R01HL142791-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10388261. Licensed CC0.

---

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