# Core Clinical Centers for the Blood and Marrow Transplant Clinical Trials Network

> **NIH NIH UG1** · MEDICAL COLLEGE OF WISCONSIN · 2021 · $184,800

## Abstract

Project Summary:
The MCW hematopoietic cell transplant and cell therapy (HCT CT) program proposes to contribute as a
BMT CTN Core Center based on our expertise in HCT, novel cell therapies, prior accrual history, quality
data submission, clinical trial design and novelty of scientific idea. We seek to advance the key scientific
area of gene therapy for Hemophilia A using the multi-site BMT CTN platform for a phase I-II study in
patients with Hemophilia A and refractory FVIII inhibitors. Over the past decade, our basic science group
has advanced the idea of curing severe Hemophilia A (HA) using patient’s own platelets to ectopically
express and store FVIII for release at sites of vascular injury where it can be available for clot formation.
This approach has been extensively tested in preclinical syngeneic and xenograft mouse models, canine
models, human primary cells and cell lines with great success. The proposed idea is a phase I-II, first in
human, gene therapy study using reduced intensity conditioning HCT to engraft a gene modified
autologous graft capable of producing platelets that express and store FVIII. The gene modified
autologous graft is produced by CD34 cell selection of an autologous apheresis product, followed by
transduction with a lentiviral vector carrying the B domain deleted form of FVIII under the control of an
ITGA2B promoter. We hypothesize that following engraftment of the gene modified graft, lineage specific
expression of FVIII gene in the megakaryocyte lineage will lead to a proportion of circulating platelets
synthesizing and storing FVIII. Platelets  granules containing FVIII (an immune privileged site) will
provide FVIII at the sites of vascular injury where platelet aggregation and activation occurs. This approach
limits the immunogenicity of FVIII without limiting availability, can induce tolerance and restore hemostasis
in subjects with inhibitors without the need for FVIII bypassing agents or tolerizing FVIII infusions. This
early phase trial is limited to those with refractory inhibitors to FVIII, a subgroup with no effective
therapy and area of significant unmet need. In preclinical tests, platelet FVIII expression was highly
effective at producing hemostasis even in those with high titer inhibitors, was not associated with
thrombosis or mutagenesis and was able to lower inhibitor titers. We believe the use of lower intensity
conditioning will be safe rendering this a major innovation in the field and with potential future
application to FVIII gene in HA patients without inhibitors, severe von Willebrand’s disease and other
transgenes in platelet receptor disorders.

## Key facts

- **NIH application ID:** 10187640
- **Project number:** 5UG1HL138641-05
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Saurabh Chhabra
- **Activity code:** UG1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $184,800
- **Award type:** 5
- **Project period:** 2017-07-27 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10187640

## Citation

> US National Institutes of Health, RePORTER application 10187640, Core Clinical Centers for the Blood and Marrow Transplant Clinical Trials Network (5UG1HL138641-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10187640. Licensed CC0.

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