Novel approach to cellular transplantation may be helpful with hemophilia

A team of researchers from the University of Notre Dame’s W.M. Keck Center for Transgene Research and Department of Chemistry and Biochemistry has developed a novel cellular transplantation technique that may alleviate immune responses complicating treatments for hemophiliacs. The technique is described in a paper in this month’s inaugural issue of the Journal of Thrombosis and Haemostasis.

Led by Elliot D. Rosen, associate director of the Keck Center, the Notre Dame researchers studied mice that lacked the gene for Factor X, an essential clotting protein. Approximately 30 percent of Factor X-deficient embryos die before term and the remaining animals survive to term but die shortly after birth due to abdominal or brain hemorrhage. In humans, Factor X-deficiency is an inherited disorder that causes abnormal bleeding due to a lack of the protein.

Since Factor X— as well as several other coagulation proteins— is made by the liver, the Notre Dame scientists explored the possibility of transplanting normal liver cells to correct the defect. Using an in utero transplantation approach, the researchers isolated fetal liver cells from embryonic mice that synthesized Factor X. These cells were transplanted into the peritoneal cavities of the Factor X-deficient fetuses. The donor cells were found in approximately 50 percent of the livers of mice who received the transplants in utero.

Most importantly, unlike untreated Factor X-deficient mice that died shortly after birth, those mice that incorporated the donor cells were rescued and survived long term. The transplanted liver cells were detected in 47 percent of the livers of adult mice and were also recovered in the bone marrow, spleen, lung and, occasionally, in the brain and testis.

In utero cell transplantation could potentially offer an effective therapeutic strategy for treating hemophilia. Hemophilia is a group of hereditary bleeding disorders in which patients fail to produce a functional, or sufficient, quantity of at least one essential blood clotting protein. The disorder results in spontaneous bleeding, particularly in joints, muscles and internal organs.

Historically, hemophilia has been linked to royalty. However, one in 10,000 male births worldwide is hemophilic.

 The treatment of hemophilia and related clotting disorders has been largely based on replacing the missing clotting factor with a substitute, typically obtained from human plasma or, more recently, recombinant, or genetically engineered, preparations. However, because they are foreign proteins, more than 15 percent of patients develop antibodies or “inhibitors” to the clotting factor substitutes and become resistant to further treatment.

 The Notre Dame scientists reasoned that by implanting the fetal liver cells into the embryo before the development of the mouse’s immune system, the Factor X made by the donor cells would be recognized by the mouse as its own and would not trigger an immune reaction. Furthermore, the donor cells continuously produce the missing coagulation factor and should eliminate the need to continually inject the therapeutic protein.

Originally published by William G. Gilroy at on January 21, 2003.