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

  • Author(s): Rose, Melanie;
  • Gao, Kewa;
  • Cortez-Toledo, Elizabeth;
  • Agu, Emmanuel;
  • Hyllen, Alicia A;
  • Conroy, Kelsey;
  • Pan, Guangjin;
  • Nolta, Jan A;
  • Wang, Aijun;
  • Zhou, Ping
  • et al.

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.

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