Stem cells to the rescue in hemophilia

DURHAM, N.C.—In a new study released in STEM CELLS Translational Medicine (SCTM) under the title “Endothelial Cells Derived from Patients’ Induced Pluripotent Stem Cells for Sustained FVIII Delivery and the Treatment of Hemophilia A,” researchers at the University of California, Davis (UC Davis) and the Chinese Academy of Science demonstrated how induced pluripotent stem cells can provide a renewable supply of endothelial cells. These cells can then be genetically modified to produce high levels of a clotting protein that was used to successfully treat hemophilia A in mice.

“The culprit behind hemophilia A is a protein called factor VIII (FVIII), which is responsible for blood clotting,” explained Dr. Ping Zhou of UC Davis’ Stem Cell Program, co-lead investigator on the new study. “In hemophilia A patients, we find that this protein is either defective or missing altogether.”

Currently, the standard treatment for hemophilia A involves repeated infusions of recombinant FVIII proteins. However, this treatment has multiple challenges. Infusion of the FVIII protein can treat, but not cure the disease. Also, the treatments must be given two to three times a week, so long-term they can be inconvenient and pose a risk of infection. In addition, this treatment is extremely costly—the median price is $98,334 annually, according to a study published in the Journal of Medical Economics—and it is a lifelong expense. “Furthermore, bleeding episodes are still common even with factor replacement therapy due to the fluctuation of the infused FVIII levels,” said Dr. Aijun Wang of the UC Davis School of Medicine and the other lead investigator on the study.

Cell therapy is actively being studied as a potential alternative therapy for hemophilia A. Multiple cell types have been tested for the delivery of FVIII in vivo with promising results. However, some major challenges remain—mainly, finding a sufficient supply of the therapeutic cells and a way to sustain their engraftment.

In the study published in SCTM, the researchers explored endothelial cells (ECs) derived from hemophilia A patients’ induced pluripotent stem cells (HA-iPSC-ECs) as a way to deliver FVIII.

“FVIII is primarily produced in ECs in a non-diseased human being, so this means that ECs hold great potential for development as a cell therapy for hemophilia A,” Wang explained. “Also, since hemophilia A is a genetic disease, a child born with the disease needs to be treated early in life. Therefore, we assessed the engraftment of the HA-iPSC-ECs at the neonatal stage in comparison to the adult stage, an analysis not previously studied. Finally, we assessed the functionality of the human HA-iPSC-ECs in attenuating hemophilia.”

To conduct their study, they collected cells from patients with hemophilia A, induced them to become induced pluripotent stem cells and then ECs and genetically modified the cells to express high levels of FVIII.

“Not only did the results produce an ample supply of ECs, but when we tested how the HA-iPSC-ECs affected mice with hemophilia A, we found they were indeed capable of durable engraftment in both neonatal and adult animals,” Zhou reported. “We also found that the FVIII in the cells functionally corrected or alleviated the animals’ hemophilia A symptoms.

“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 HA-iPSC-derived ECs can serve as an autologous cell factory to deliver FVIII for treating hemophilia A in adults and newborns, too.”

“The findings emerging from this study are interesting and useful. The opportunity of using iPSCs as a source of factor VIII-producing cells that have the potential to treat hemophilia A is appealing and needs to be explored further for a potential clinical application,” said Dr. Anthony Atala, editor-in-chief of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine.