Scientists at the Albert Einstein College of Medicine of Yeshiva University have shown for the first time that transplanted cells can cure hemophilia A (the most common form of the disease) in an animal model.
Their study appears online February 14 in the Journal of Clinical Investigation.
Hemophilia A affects one in 10,000 males and is characterized by recurrent, spontaneous bleeding that can cause disability or death. It has, most famously, affected British and Russian nobility, along with countless others. The Einstein team, led by Dr. Sanjeev Gupta, cured hemophilia A by transplanting healthy liver endothelial cells from donor mice into a mouse model of the disease. In curing these mice, the Einstein researchers also overturned conventional wisdom regarding which cells produce factor VIII, the crucial clotting protein that is lacking in people with type A hemophilia.
“We've known for three decades that factor VIII is produced in the liver, but precisely where has been controversial,” says Dr. Gupta, a professor in the departments of medicine and pathology at Einstein. “It was assumed that factor VIII was made by the hepatocytes—cells that perform many of the liver's functions and comprise most of its bulk. But our research had suggested that the primary sources were special endothelial cells that line the sinusoids, the liver's blood-filled spaces. We did this study to confirm the role of liver endothelial cells in producing factor VIII and to see if transplanting them from a healthy donor liver could correct hemophilia A in an animal model.”
The donor mice used by Dr. Gupta's team had been genetically engineered so that their endothelial cells expressed the gene for green fluorescent protein. This allowed the researchers to see whether the liver endothelial cells—isolated from donor livers and then injected into a vein leading into the liver of recipient hemophilia A mice—could successfully engraft within the recipients' livers. Before transplantation, to “make room” for the donated cells to engraft and proliferate, the researchers gave recipient mice a dose of the toxic chemical monocrotaline to deplete their native liver endothelial cells.
“Three months after transplantation, when we examined the livers of recipient mice, we found that the transplanted cells had engrafted and increased in number,” says Dr. Antonia Follenzi, an instructor in pathology at Einstein and the lead author of the study. “Even more important, those mice with the most transplanted cells in their livers produced factor VIII in sufficient amounts to completely correct their hemophilia A.”
Efforts up until now to cure hemophilia—ranging from faith healing by the Russian monk Rasputin early in the 20th century to clinical trials in the U.S. using gene therapy—have had limited or no success. While the Einstein study marks a significant advance against hemophilia A, Dr. Gupta cautions that more work is necessary before liver-cell transplants can be attempted on people. “An important need,” he says, “is for safer alternatives to monocrotaline, the chemical we gave to recipient mice to create space for healthy donor liver cells. Fortunately, several drugs already in clinical use hold promise in that regard.”
The principle established by this study—selectively injuring native endothelial cells and replacing them with healthy donor endothelial cells—might also help in treating hemophilia B (the less common form of the disorder) and, more broadly, aid in “tissue engineering” in the many other areas of the body where endothelial cells are found, says Dr. Gupta. For example, he notes that endothelial cells isolated from blood vessels and transplanted into the heart could help in treating cardiovascular disease. In addition, he says that it may be possible to deliver therapeutic substances into the liver and other organs by combining gene therapy with the cell-transplantation approach used in this study.
Daniel Benten and Phyllis Novikoff of Einstein were also involved in this study. Other collaborators were Louisa Faulkner and Sanj Raut of the National Institute for Biological Standards and Control, Hertfordshire, United Kingdom. The study was funded in part by The National Institute of Diabetes and Digestive and Kidney Diseases.