Endothelial cells — those that line the inside of blood vessels — derived from stem cells of people with hemophilia A and modified to produce functional factor VIII were able to ease blood loss in a mouse model of the disease, a study reported.
These findings support the potential of induced pluripotent stem cells to be a patient-specific cell therapy for hemophilia A, its researchers said.
The study, “Endothelial cells derived from patients’ induced pluripotent stem cells for sustained factor VIII delivery and the treatment of hemophilia A,” was published in the journal Stem Cells Translational Medicine.
Hemophilia A is characterized by the lack of factor VIII (FVIII), a blood-clotting protein normally produced from the F8 gene.
Standard treatments are based on factor replacement, in which patients receive repeat infusions of recombinant (lab-made) FVIII proteins in an attempt to restore the factor’s normal levels and activity in the blood. While effective, these treatments do not cure the disease, are costly, and can increase the risk of infections.
“Furthermore, bleeding episodes are still common even with factor replacement therapy due to the fluctuation of the infused FVIII levels,” Aijun Wang, PhD, with the University of California Davis School of Medicine and a study lead investigator, said in a press release.
“Gene and cell therapies have great potential to treat HA [hemophilia A], because if these therapies can increase plasma FVIII levels only to above 1% to 5% of normal FVIII levels, spontaneous bleeding episodes can be markedly reduced,” the scientists wrote.
However, cell and gene therapies must overcome several challenges, the study noted, including the short supply of genetically engineered therapeutic cells and questions as to their long-term effectiveness or engraftment abilities.
FVIII is mainly produced by cells known as endothelial cells (ECs), which line the inside of blood vessels. Cell therapy using these cells could be an effective alternative treatment.
Researchers at UC Davis started by creating two lines of induced pluripotent stem cells (iPSCs) derived from two hemophilia A patients. Of note, iPSCs are adult cells that can be reprogrammed back to a stem cell state to generate any type of human cell.
They then differentiated the patient-derived iPSCs into ECs that had been genetically engineered to produce large amounts of FVIII.
Investigators injected the modified ECs into the muscles of neonatal and adult mice that lacked a functional immune system. They found that, in both groups, the transplanted cells survived and grew inside the animals for at least 10 to 16 weeks, leading to the consistent production of FVIII.
Finally, they tested the potential cell therapy in a mouse model of hemophilia A, which lacked a working F8 gene (F8 knock-out mice).
When transplanted into these mice, the modified ECs significantly reduced blood loss — assessed in a bleeding test in which the animals’ tail was clipped — and increased FVIII levels in the blood to between 11.2% and 369.2% of its standard value in humans at two weeks post transplant.
“We also found that the FVIII in the cells functionally corrected or alleviated the animals’ hemophilia A symptoms,” said Ping Zhou, PhD, co-lead investigator of the study.
“As such, we believe that this study is a significant step forward in developing a cell therapy for hemophilia A, and that it provides proof-of concept that [genetically engineered] ECs can serve as an autologous [self] cell factory to deliver FVIII for treating hemophilia A in adults and newborns, too,” Zhou added.
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