Investigating Optimal Autologous Cellular Platforms for Prenatal or Perinatal Factor VIII Delivery to Treat Hemophilia A

• Type of Material: Article
• Authors: Christopher Stem, Wake Forest School of Medicine; Christopher Rodman, Wake Forest School of Medicine; Ritu M Ramamurthy, Wake Forest School of Medicine; Sunil George, Wake Forest School of Medicine; Diane Meares, Wake Forest School of Medicine; Andrew Farland, Wake Forest School of Medicine; Anthony Atala, Wake Forest School of Medicine; Christopher D Porada, Wake Forest School of Medicine; H Trent Spencer, Emory University; Christopher Doering, Emory University; Graça Almeida-Porada, Wake Forest School of Medicine
• Language: English
• Date: 2021-08-10
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Stem, Rodman, Ramamurthy, George, Meares, Farland, Atala, Doering, Spencer, Porada and Almeida-Porada.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fcell.2021.678117
• Title of Journal or Parent Work: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
• Volume: 9
• Start Page: 678117
• End Page: 678117
• Grant/Funding Information: This work was supported by NIH, NHLBI grants: HL130856, HL135853, and HL148681.
• Keywords: VON-WILLEBRAND-FACTOR; IN-UTERO TRANSPLANTATION; AMNIOTIC-FLUID; hemophilia A; COAGULATION-FACTOR-VIII; Cell Biology; endothelial progenitor cell; Developmental Biology; Science & Technology; gene therapy; HIGH-LEVEL EXPRESSION; Life Sciences & Biomedicine; ENDOTHELIAL-CELLS; FVIII; mesenchymal stromal (stem) cell therapy; GENE-THERAPY; MESENCHYMAL STEM-CELLS; PHENOTYPIC CORRECTION; PROGENITOR CELLS
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology

Abstract

Patients with the severe form of hemophilia A (HA) present with a severe phenotype, and can suffer from life-threatening, spontaneous hemorrhaging. While prophylactic FVIII infusions have revolutionized the clinical management of HA, this treatment is short-lived, expensive, and it is not available to many A patients worldwide. In the present study, we evaluated a panel of readily available cell types for their suitability as cellular vehicles to deliver long-lasting FVIII replacement following transduction with a retroviral vector encoding a B domain-deleted human F8 transgene. Given the immune hurdles that currently plague factor replacement therapy, we focused our investigation on cell types that we deemed to be most relevant to either prenatal or very early postnatal treatment and that could, ideally, be autologously derived. Our findings identify several promising candidates for use as cell-based FVIII delivery vehicles and lay the groundwork for future mechanistic studies to delineate bottlenecks to efficient production and secretion of FVIII following genetic-modification.