# Prenatal Cell and Gene Therapy for Hemophilia A

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2020 · $698,903

## Abstract

Project Summary
Intrauterine stem cell transplantation (IUTx) using a minimally invasive, ultrasound-guided approach has been
performed in ~50 human patients for 14 different genetic disorders, proving that this procedure poses minimal
risk to both the fetus and the mother. Hemophilia A (HA) is an ideal disease to be treated by IUTx, since 75%
of HA cases can be diagnosed through prenatal screening. IUTx could be curative, or at least convert severe
HA to a moderate/mild phenotype, significantly reducing the need for FVIII infusions. Importantly, exposure to
vector-encoded FVIII during early immunologic development would induce tolerance FVIII and avoid formation
of inhibitors, the most serious and threatening complication in HA treatment. Indeed, recent studies showed in
both severe and non-severe HA patients, that the development of FVIII inhibitors is associated with increased
risk of death. Using the same preclinical animal model, that allowed the delineation of the conditions used in
clinical IUTx, we showed that prenatal infusion of transduced bone marrow stromal progenitor cells (MSPs)
resulted in robust long-term, multi-organ integration into both parenchyma and vasculature, long-term release
of secreted transgene products into the circulation, and development of immune tolerance. Using the same
sheep model, similar results were obtained after IUTx of amniotic fluid-derived stromal progenitors (AFPs).
Utilizing a line of sheep that emulates the genetics, inhibitor formation, and clinical symptoms of the severe
form of human HA, we showed that the postnatal transplantation of paternal (haploidentical) MSPs engineered
to express high levels of FVIII led to complete phenotypic correction of two pediatric HA sheep, reversal of
existing hemarthroses, and return to normal physical activity. However, like with FVIII infusions in human
patients, these two sheep developed FVIII inhibitors following postnatal treatment. This work thus provides
compelling evidence that the transplantation of FVIII-expressing stromal cells could be curative for HA, if
inhibitor formation could be avoided. Therefore, we hypothesize that using an IUTx-based strategy to treat HA
will overcome the two major shortcomings that have been observed following factor replacement therapy and
current gene therapy approaches to treat HA, namely a lack of sustained FVIII expression and immunologic
responses to the therapeutic protein. We propose to: 1) determine the ideal cell source to obtain the highest
long-term engraftment levels and the in vivo distribution patterns that maximize release of FVIII into the
circulation; 2) use HA sheep to demonstrate that an IUTx approach using the optimal cell source and FVIII
transgene construct, can be curative, or at least permanently convert severe HA to a mild phenotype; 3) test
whether receiving IUTx precludes inhibitor induction following postnatal FVIII infusion and/or induces tolerance
that persists even after postnatal challenge with ...

## Key facts

- **NIH application ID:** 10014648
- **Project number:** 5R01HL135853-04
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Graca Duarte Almeida-Porada
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $698,903
- **Award type:** 5
- **Project period:** 2017-07-14 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10014648

## Citation

> US National Institutes of Health, RePORTER application 10014648, Prenatal Cell and Gene Therapy for Hemophilia A (5R01HL135853-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10014648. Licensed CC0.

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