# cGMP Manufacture Of FVIII-Expressing Placental Cells For Hemophilia A

> **NIH NIH U01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2020 · $383,839

## Abstract

PROJECT SUMMARY
Current treatments for hemophilia A consist of frequent FVIII infusions to maintain hemostasis. Replacement
therapy is lifelong, expensive, unavailable for ~75% of the world's hemophiliacs, and >30% of patients develop
inhibitors to Factor VIII (FVIII). There is thus a critical need to develop affordable HA therapies with longer-
lasting benefit or permanent cure. Clinical trials directly infusing AAV vectors for in vivo FVIII gene delivery
have yielded promising results in adults, but pre-existing neutralizing antibodies (NAbs) to AAV are present in
up to 50% of the population and inhibit target cell transduction when AAV is delivered systemically. As a
result, clinical trials using AAV can currently only enroll subjects with no- or low-titer pre-existing AAV NAbs.
Prenatal treatment (PNTx) for hemophilia A would circumvent the immune barriers present in adult patients,
and could induce lifelong tolerance to FVIII, and thereby eliminate the risk of FVIII inhibitor formation, the most
feared problem in treatment/management of hemophilia A. Although direct injection of viral vectors into
prenatal recipients would likely be successful, numerous safety concerns need to be addressed before this
approach can enter the clinic. A cell and gene therapy-based approach, in which cells are transduced in vitro,
would enable multiple safeguards to be implemented in production, e.g., copy number and integration site
analyses, that are not possible with direct vector injection. Such an approach would also eliminate the
possibility of off-target gene-modification. Using a large animal model of PNTx, we showed that an off-the-shelf
therapy comprised of human placental cells (PLCs) transduced with a lentiviral vector (LV) encoding a
bioengineered, codon-optimized FVIII transgene, designated mcoET3, resulted in plasma FVIII activity levels
that exceeded that of control non-transplanted animals by over 20%, and that these levels were maintained for
at least 1 year after birth. Based on these results, a Pre-IND meeting with the FDA was held to discuss the
path to a clinical trial. It was agreed that while it was vital to consider safety of the product to safeguard the
patient, it was also imperative to protect the mother, particularly with respect to possible exposure to the gene-
modified cells and/or gene product. To directly address this FDA guidance, we herein propose to: Aim 1:
Manufacture, characterize, and authenticate, in vitro, a gene-modified PLC-based hemophilia A therapeutic
product under cGMP conditions; and Aim 2: Confirm the therapeutic potential and safety of mcoET3-
expressing human PLCs in vivo, in mice and in a large animal model of PNTx, determine whether there is
transfer of the product across the placenta to the mother following PNTx, and if so, define the immune
consequences of such transfer. At the completion of this project, we expect to have demonstrated the
innocuity of the PNTx approach, and to have developed a safe and eff...

## Key facts

- **NIH application ID:** 9951108
- **Project number:** 5U01HL148681-02
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Graca Duarte Almeida-Porada
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,839
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9951108

## Citation

> US National Institutes of Health, RePORTER application 9951108, cGMP Manufacture Of FVIII-Expressing Placental Cells For Hemophilia A (5U01HL148681-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9951108. Licensed CC0.

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