ORIGINAL RESEARCH article
Front. Immunol.
Sec. Alloimmunity and Transplantation
This article is part of the Research TopicMethods in Alloimmunity and Transplantation: 2025View all 11 articles
Transplanted Gene-Modified Placental Cells Boost FVIII Activity in Pediatric Sheep without Eliciting Immunity, Toxicity, or Adverse Events
Provisionally accepted
Brady Trevisan1Martin Rodriguez1
Ritu Ramamurthy1Sunil George1
Oluwaseun O. Babatunde1Jacqueline Dizon1Jordan Shields2,3Shannon Lankford1Denise Schwahn4
Michael Gautreaux5Andrew Farland5John Owen5Anthony Atala1,3
Christopher Doering2,3
H. Trent Spencer2,3Christopher D. Porada1
Graca Almeida-Porada1*- 1Regenerative Medicine, Wake Forest Institute for Regenerative Medicine, School of Medicine, Wake Forest University, Winston-Salem, United States
- 2Children's Healthcare of Atlanta Inc Aflac Cancer and Blood Disorders Center, Atlanta, United States
- 3Emory University Department of Pediatrics, Atlanta, United States
- 4Wave Life Sciences, Cambridge, United States
- 5Wake Forest University School of Medicine, Winston-Salem, United States
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Background: The current standard of care for Hemophilia A (HA), a hereditary bleeding disorder caused by mutations in the Factor VIII (F8) gene, include FVIII replacement proteins, engineered clotting factors, and a broad array of new therapeutics including antibodies and gene therapy. These therapies allow persons with HA (PHA) to have near normal life expectancies, but the burden of disease continues to be high, with 30% of PHA developing FVIII inhibitors, considerably increasing the risk of morbidity and mortality. Objective: The present study tested the ability of human placental cells (PLC), transduced with a lentivector encoding a codon-optimized, bioengineered FVIII transgene (mcoET3) (PLC-mcoET3) to increase FVIII activity levels after administration to pediatric large animals. In addition, we determined whether administration of PLC-mcoET3 would induce inhibitor formation, and defined how the immune response to infused human FVIII (hFVIII) or ET3 proteins differed from that of administration of PLC-mcoET3. Methods: Pediatric sheep at 8-12 months of age were used in this study. PLC-mcoET3 providing 20 IU/kg of ET3/infusion/sheep were administered intravenously (IV) or intraperitoneally (IP), and control groups received the same dose/kg of purified recombinant ET3 or human full-length recombinant FVIII protein (hFVIII). Plasma FVIII activity, presence of anti-FVIII/ET3 humoral or cellular immune responses, and immunologic responses using a multiplexed gene expression panel were assessed. Results and Conclusion: Data show that while intravenous (IV) infusion of ET3 or hFVIII to pediatric sheep results in a high level of inhibitory antibodies, administration of PLC-mcoET3 IV is safe, and resulted in increased plasma FVIII activity for at least 15 weeks without the formation of anti-ET3/FVIII inhibitory antibodies.
Keywords: Hemophilia A, FVIII, Gene Therapy, Mesenchymal stromal cell, Transplantation, Placental cells, Exosomes, FVIII inhibitors
Received: 01 Oct 2025; Accepted: 11 Nov 2025.
Copyright: © 2025 Trevisan, Rodriguez, Ramamurthy, George, Babatunde, Dizon, Shields, Lankford, Schwahn, Gautreaux, Farland, Owen, Atala, Doering, Spencer, Porada and Almeida-Porada. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Graca Almeida-Porada, galmeida@wakehealth.edu
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