In recent years, Stanford Children’s Hospital has made a name for itself as one of the world’s leading centers for treating Fanconi Anemia (FA), a terrible genetic disorder that makes children and young adults susceptible to various cancers and nearly always leads to the collapse of the cell population responsible for the blood and immune system. Untreated, FA patients have an average life expectancy of only 10 years.

Through tenacious scientific research, Stanford physician-scientists have devised innovative solutions for improving the treatment of FA patients. Stanford researchers are now conducting one clinical trial of genetically engineered stem cells to treat the disorder. Another clinical trial at Stanford focuses on using antibodies to prepare FA patients for stem cell transplantation instead of chemotherapy or irradiation, which can be damaging.   

Currently, the most effective treatment for FA is a blood stem cell transplantation from an immunologically matched donor, but that process still entails significant risks. First, the patient needs to be treated with drugs that destroy their immune system, so their own body does not reject the donor cells. These drugs also cause widespread tissue damage. After transplantation with donor stem cells, immune cells arising from the transplanted cells can attack patients’ own tissue, a disorder called graft-versus-host disease. Drugs that suppress this immune activity can themselves be harmful and increase the risk of cancer.

“We are having some success in developing techniques to reduce the impact of pre-transplant conditioning and manage immunological complications,” said institute member Agnieszka Czechowicz, MD, PhD, an assistant professor of Pediatrics in the School of Medicine. “But the goal is to make these therapies for FA, safe for these kids.”  

Agnieszka and her colleagues have recently tested an innovative solution that may allow them to sidestep many of the problems that result from treating FA with donor stem cells. In a research article published in July in the journal Blood Advances, Czechowicz and her colleagues showed that by transplanting blood stem cells prenatally in a mouse model of FA, the disease could be treated effectively and without the usual immunological or drug complications. Czechowicz was the senior author on the paper. Researcher Leah Swartzrock was the first author.

“Maintaining a pregnancy requires the fetus to have immune tolerance to the mom’s cells,” Czechowicz said. “Because of this, transplanting stem cells prenatally can potentially be successful without pre-transplant conditioning and without damaging the immune system. This could stabilize the blood system in FA patients for a lifetime without use of toxic drugs or immunological complications.”

Testing this idea turned out to be challenging. Mice with full-on FA are infertile, so mice with one FA gene were crossed with a mate that also was a carrier and had only one FA gene, producing a mixed litter of mice, only some of which had the double FA genotype necessary to cause the disease. Secondly, injecting fetal mice with stem cells required a lot of technical finesse. “While this treatment could be performed clinically in patients relatively simply, in a way that is similar to a common prenatal red blood cell transfusion, treating tiny fetal mice is much more challenging,” Swartzrock said.

The results were exciting, the researchers said. After prenatal transplantation, 27% of the blood and immune cells in the mice came initially from the donor. What’s more, this percentage grows. “Even if there is just a little engraftment, over time that percentage of donor cells grows to nearly 100%,” Czechowicz said.

“FA is really unique in that FA stem cells are dysfunctional in a way that gives healthy stem cells a competitive advantage,” Czechowicz said. “As a result, donor stem cells will slowly replace the native population of stem cells with the FA gene mutations.” So even a partial replacement of FA stem cells with healthy stem cells leads to a stabilization of the stem cell population, she said.

Mice that received the stem cell transplants in the womb also did not display any immune complications after birth, meaning that anti-rejection drugs were not necessary to avoid immunologic rejection and graft-versus-host disease did not develop, the researchers found.  

“This has the potential to be an easy, one-time treatment that lasts a lifetime, with no hospitalization required,” Czechowicz said.

The investigators are now planning on moving forward to develop this treatment in human clinical trials, they said.

The research was funded by the Fanconi Cancer Foundation (formerly called the Fanconi Anemia Research Fund), and the Stanford University School of Medicine Dunlevie MaternalFetal Medicine Center for Discovery, Innovation and Clinical Impact.