Treating Genetic Disorders Before Birth

Researchers are working on transplanting stem cells in utero.

Physicians may one day be able to treat genetic blood diseases before a child is even born. In a study of mice that was published this week in the Journal of Clinical Investigation, researchers at the University of California, San Francisco, have found that transplanting a mother’s own stem cells into her fetus populates its bone marrow with healthy cells while avoiding immune rejection.

Fortifying the fetus: By studying the immune systems of 14-day-old mouse embryos (shown here in an ultrasound), researchers have shown that genetic blood disorders might be treatable before birth.

If the findings hold true in humans, stem-cell transplants from mother to fetus could prime the fetus for a bone-marrow transplant from its mother—or a donor that is tissue-matched to the mother—after birth.

Diseases such as sickle cell anemia and beta thalassemia result from abnormal red blood cells and can be treated with bone-marrow transplants. But it’s not always possible to find a match.   And standard bone-marrow transplants, even between tissue-matched donors, must be followed with a lengthy course of immunosuppressive drugs.

Scientists theorize that bone-marrow transplants performed when a fetus is still developing would override this problem. They suspect that the fetus’s immature immune system could be tricked into adopting those foreign cells and recognizing them as its own. “The fetus is wired to tolerate cells—when it encounters cells from mom, it tolerates them,” says Tippi MacKenzie, the pediatric surgeon at UCSF who led the new research.

Research in animals has shown the promise of that approach. But early tests in humans came up against a serious setback—the donor cells were being rejected and killed off before a fetus could assimilate them, and no one was quite sure why. “It’s a conundrum,” says MacKenzie.

The blame, it seems, may be mom’s. MacKenzie and her colleagues found that when they injected a fetus with hematopoietic stem cells (which populate bone marrow and give rise to blood cells) that were not matched to the mother or fetus, the infusion prompted an influx of maternal immune cells into the fetus.

“What we saw was that it’s not the fetal immune system that’s rejecting the cells—it’s the mother’s,” MacKenzie says. “And if it’s the mother’s immune system that’s rejecting them, we may be able to transplant maternal cells for some of these disorders and get them to engraft.” Indeed, when researchers injected the fetus with stem cells from a donor that was tissue-matched to the mother, the cells happily took root in the fetus’s bone marrow.

“The critical question is how this applies to large animals and humans,” says Alan Flake, a pediatric surgeon and the director of the Center for Fetal Research at the Children’s Hospital of Philadelphia. Part of the issue with humans is that even when adult stem cells do survive in the fetus, it’s difficult for them to compete with the resident fetal stem cells, which can proliferate much more rapidly.

But Flake, who pioneered the fetal-stem-cell transplant treatment for severe combined immunodeficiency disease (SCID), or “bubble boy syndrome,” says that although a single dose of maternal or maternally matched donor cells might not cure disease, it could prime the fetus’s immune system into accepting a stem-cell transplant from the same person later in life.  (Fetal transplants work in SCID because the disease causes such a severe lack of immunity that a fetus can fully incorporate stem-cell transplants without competition from preëxisting immune cells.)

“This might allow us to perform in-utero transplantation to fetuses in a way that is more likely to work, and to do it in a way that could be safer to the fetus,” says Joseph (Mike) McCune, a professor of experimental medicine at UCSF who was not involved in the study.  

The next step, MacKenzie says, will be to test the treatment in larger mammals and nonhuman primates. But for now, her lab is more focused on understanding precisely what’s going on in the maternal-fetal immune system interactions. “We’re trying to figure out the mechanism by which the mother cells are exerting their effect. And we’re looking at the idea of immune-cell trafficking between mom and fetus—to what extent does it happen in human pregnancies?”

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