Transplanting FVIII/ET3-secreting cells in fetal sheep increases FVIII levels long-term without inducing immunity or toxicity

• Type of Material: Article
• Authors: Martin Rodriguez, Wake Forest School of Medicine; Brady Trevisan, Wake Forest School of Medicine; Ritu M Ramamurthy, Wake Forest School of Medicine; Sunil K George, Wake Forest School of Medicine; Jonathan Diaz, Wake Forest School of Medicine; Jordan Alexander, Emory University; Diane Meares, Wake Forest School of Medicine; Denise J Schwahn, Wave Life Sciences, Lexington; David R Quilici, University of Nevada Reno; Jorge Figueroa, Wake Forest School of Medicine; Michael Gautreaux, HLA/Immunogenetics and Immunodiagnostics Laboratories; Andrew Farland, Wake Forest School of Medicine; Anthony Atala, Wake Forest School of Medicine; Christopher B Porada, Wake Forest School of Medicine; H Trent Spencer, Emory University; Christopher D Porada, Wake Forest School of Medicine; Graça Almeida-Porada, Wake Forest School of Medicine
• Language: English
• Date: 2023-07-14
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-023-39986-1
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 14
• Issue: 1
• Start Page: 4206
• End Page: 4206
• Keywords: HEMOPHILIA-A; FACTOR-VIII; MASS-SPECTROMETRY; Science & Technology - Other Topics; INHIBITORS; EXPRESSION; GENE-THERAPY; IN-UTERO TRANSPLANTATION; Multidisciplinary Sciences; Science & Technology; TOLERANCE; MORTALITY; INDUCTION
• Research Categories: Biology, Cell; Health Sciences, Immunology

Abstract

Hemophilia A is the most common X-linked bleeding disorder affecting more than half-a-million individuals worldwide. Persons with severe hemophilia A have coagulation FVIII levels <1% and experience spontaneous debilitating and life-threatening bleeds. Advances in hemophilia A therapeutics have significantly improved health outcomes, but development of FVIII inhibitory antibodies and breakthrough bleeds during therapy significantly increase patient morbidity and mortality. Here we use sheep fetuses at the human equivalent of 16–18 gestational weeks, and we show that prenatal transplantation of human placental cells (107–108/kg) bioengineered to produce an optimized FVIII protein, results in considerable elevation in plasma FVIII levels that persists for >3 years post-treatment. Cells engraft in major organs, and none of the recipients mount immune responses to either the cells or the FVIII they produce. Thus, these studies attest to the feasibility, immunologic advantage, and safety of treating hemophilia A prior to birth.