Endothelial cells derived from patients' induced pluripotent stem cells for sustained factor VIII delivery and the treatment of hemophilia A

Melanie Rose, Kewa Gao, Elizabeth Cortez-Toledo, Emmanuel Agu, Alicia A. Hyllen, Kelsey Conroy, Guangjin Pan, Jan A. Nolta, Aijun Wang, Ping Zhou

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Hemophilia A (HA) is a bleeding disorder characterized by spontaneous and prolonged hemorrhage. The disease is caused by mutations in the coagulation factor 8 gene (F8) leading to factor VIII (FVIII) deficiency. Since FVIII is primarily produced in endothelial cells (ECs) in a non-diseased human being, ECs hold great potential for development as a cell therapy for HA. We showed that HA patient-specific induced pluripotent stem cells (HA-iPSCs) could provide a renewable supply of ECs. The HA-iPSC-derived ECs were transduced with lentiviral vectors to stably express the functional B domain deleted F8 gene, the luciferase gene, and the enhanced green fluorescent protein gene (GFP). When transplanted intramuscularly into neonatal and adult immune deficient mice, the HA-iPSC-derived ECs were retained in the animals for at least 10-16 weeks and maintained their expression of FVIII, GFP, and the endothelial marker CD31, as demonstrated by bioluminescence imaging and immunostaining, respectively. When transplanted into HA mice, these transduced HA-iPSC-derived ECs significantly reduced blood loss in a tail-clip bleeding test and produced therapeutic plasma levels (11.2%-369.2%) of FVIII. Thus, our studies provide proof-of-concept that HA-iPSC-derived ECs can serve as a factory to deliver FVIII for the treatment of HA not only in adults but also in newborns.

Original languageEnglish (US)
JournalStem Cells Translational Medicine
DOIs
StateAccepted/In press - Jan 1 2020

Keywords

  • cell therapy
  • endothelial cells
  • FVIII
  • gene therapy
  • hemophilia
  • iPSCs

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

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