Induced pluripotent stem cells show success in treating hemophilia A in mice

In a new study released in STEM CELLS Translational Medicine (SCTM), researchers at the University of California, Davis and the Chinese Academy of Science demonstrate 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 haemophilia A in mice.

Hemophilia A is a disorder in which the blood does not clot normally, causing people with the condition to bleed more than normal after an injury or surgery. In the most severe cases, this can lead to disability or death.

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

Currently, the standard treatment for haemophilia 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, with the median price being $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 Aijun Wang, 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 haemophilia 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 haemophilia 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 haemophilia A," Dr Wang explained. "Also, since haemophilia 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 haemophilia."

To conduct their study, they collected cells from patients with haemophilia 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 haemophilia A we found they were indeed capable of durable engraftment in both neonatal and adult animals. We also found that the FVIII in the cells functionally corrected or alleviated the animals’ haemophilia A symptoms," Dr Zhou said.

"As such, we believe that this study is a significant step forward in developing a cell therapy for haemophilia 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 haemophilia 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 haemophilia A is appealing and needs to be explored further for a potential clinical application," said Anthony Atala, Editor-in-Chief, STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine.

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