Prenatal stem cell treatment targets rare genetic disease before birth

Stanford Medicine pediatric hematologist Agnieszka Czechowicz, MD, Ph.D., has devoted her research career to improving treatments for rare blood disorders. She’s an expert in Fanconi anemia, a genetic disease that interferes with DNA repair and blood cell production. By age 12, most people with the disease experience a life-threatening complication called bone marrow failure, in which the body’s blood-cell factory stops functioning.

In recent years, Czechowicz has heard from a growing number of expectant parents who received diagnoses of Fanconi anemia during pregnancy and are wondering what lies ahead for their child.

“Often, families have been trying really hard to have a child, are excited about the pregnancy with all this optimism for this child’s life, and they’re suddenly learning about a shocking disease with treatments that are not particularly good,” said Czechowicz, an assistant professor of pediatrics. Stem cell transplant, the best available treatment, can reboot a failing blood system and save the life of a child with Fanconi anemia, but it currently comes with severe side effects, such as high risk for cancer, and requires a long hospitalization, she tells families.

Difficult conversations with these parents-to-be motivated her to investigate a new, prenatal treatment option. In collaboration with colleagues from the Dunlevie Maternal-Fetal Medicine Center and the Fetal and Pregnancy Health Program at Stanford Medicine Children’s Health, Czechowicz’s team is now opening a clinical trial of prenatal stem cell transplant, in which a pregnant mom donates healthy blood-forming stem cells that will be infused to her fetus through the umbilical cord.

Evidence from preclinical research suggests that unique features of the developing immune system may allow these prenatal transplants to circumvent the problems with traditional treatment and stabilize the disease before birth.

Czechowicz explained the science behind the new clinical trial, what her research shows about families’ receptiveness to the approach, and what her team hopes to learn as they bring the technique to the first research participants. Her answers have been edited for length and clarity.

What goes wrong in Fanconi anemia?

Fanconi anemia is a genetic disease affecting one in every 100,000 to 160,000 people worldwide that causes a deficiency in DNA repair. This causes problems when cells divide, including in the stem cells found in the bone marrow that make blood cells. In almost all patients, Fanconi anemia leads to bone marrow failure, meaning the bone marrow isn’t making the various types of blood and immune cells that the body needs.

Fanconi anemia patients with bone marrow failure have low levels of oxygen-carrying red blood cells, which can make them very tired. These kids have headaches, they’re very pale, they don’t have normal levels of energy for learning and playing. They also have low platelets—cells needed for blood clotting—which leads to a high propensity to bleeding and bruising. Patients can’t engage in sports due to potential bleeds. And Fanconi anemia patients also don’t have enough white blood cells, aka immune cells, so they can experience severe infections.

The gene mutation that causes poor DNA repair is present in every cell in the body, so patients are also at risk of developing cancers everywhere.

How has Fanconi anemia diagnosis and treatment evolved in recent years?

Historically, patients were only diagnosed when they had severe bone marrow failure or developed cancer. We use radiation and chemotherapy to treat cancer and for stem cell transplants that relieve bone marrow failure, but these toxic treatments are very hard for Fanconi anemia patients to tolerate because of their DNA repair defect.

We have been trying to identify patients earlier, treat them earlier, and offer them less-toxic therapies. Our team has been investigating gene therapy approaches and ways to offer stem cell transplants with fewer side effects. A stem cell transplant gives the patient the blood-forming cells of a healthy donor, so it relieves many aspects of the disease.

In the past, prenatal diagnosis was rare. It happened primarily because a family already had a child with the condition, and physicians performed an amniocentesis to look for it in later pregnancies.

More patients now get diagnosed during pregnancy because of improvements in prenatal care, including expanded screening for genetic diseases early in pregnancy. Fanconi anemia can also present with some subtle physical differences. Today, with improved prenatal imaging technologies, physicians may see a certain abnormality on a prenatal scan and recommend a diagnostic amniocentesis. Fluid obtained from the amniotic cavity can then be tested via whole genome sequencing and specialized breakage studies that detect telltale fragility of the chromosomes to confirm the diagnosis of Fanconi anemia.

Prenatal diagnosis opens up the possibility of prenatal treatment. What do we know about the feasibility of that approach?

We have strong evidence from animal studies that a prenatal stem cell transplant from Mom may treat Fanconi anemia without any chemo, radiation, or immune suppression. In a traditional stem cell transplant in children and adults, chemotherapy and radiation help make space in the patient’s bone marrow for the donor’s cells to establish themselves, or engraft. Strong immune suppression is also given to ensure the patient’s immune system does not reject the donor’s cells.

We conducted a study published in 2024 in which we performed stem cell transplants during pregnancy in mice, without using any medication pretreatment—no chemo, radiation, or immunosuppression. In animals that did not have Fanconi anemia, the transplants were not rejected but only had minor engraftment. But in animals with Fanconi anemia, we got very high levels of engraftment, and the maternal stem cells stayed in the fetal bone marrow and stabilized the disease after the mice were born. Another team at a different institution also tried this and found the same thing.

We think this works because, in Fanconi anemia, the fetus is already starting to experience some bone marrow failure. There is literature showing that these fetuses have lower stem cell counts, so there is space in the bone marrow for Mom’s cells.

We also have evidence that there is a unique opportunity in prenatal development for the donated maternal cells to be immunologically accepted. There are two trains of thought about why. One is that the fetal immune system is immature and less likely to attack something “foreign.” Another body of literature suggests that fetuses have special tolerance to Mom and shouldn’t immunologically reject Mom’s cells. There’s data to support both of those theories being true.

Overall, the research gives us real reason to believe prenatal transplants would stabilize the bone marrow in these patients and prevent the need for subsequent therapies. We think these kids would never need a transplant later in life, which would let them live more normal lives and avoid several months in the hospital as well as chemotherapy and radiation.

What happens in a prenatal stem cell transplant?

To collect stem cells from the pregnant mom, the physician gives her epidural anesthesia, the same type of anesthesia used during labor and delivery. The cells are collected from the mom’s pelvic bone. It’s a small amount of bone marrow, 300 milliliters, or about 10 fluid ounces.

The stem cells are extracted from the other cells in the sample and given to the fetus through an ultrasound-guided infusion into the umbilical cord. The infusion technique is the same as that used for prenatal blood transfusions.

Prenatal stem cell transplant has been tested in a human clinical trial for a different disease, alpha thalassemia major. The study showed that the prenatal stem cell transplants were safe and feasible, but, for that condition, they were not as effective as hoped. The mom’s cells did not become reliably established in the fetal bone marrow.

We think the reason is that in alpha thalassemia major, the bone marrow is really revved up, trying to compensate for severe anemia that is already affecting the fetus, so there isn’t enough space in the fetal bone marrow for Mom’s cells to become established. Because the biology of Fanconi anemia is different, and because our animal studies showed efficacy, we think Fanconi anemia is more suitable for a prenatal transplant.

There are still challenges to our planned trial. One challenge is identifying patients and getting them here early enough. We don’t broadly screen pregnancies for Fanconi anemia, so it is still unusual for families to receive a diagnosis in pregnancy.

We also don’t know the optimal window in development for this type of transplant. Our clinical trial is written for 19 to 28 weeks’ gestation, which we chose based on our animal data. But until we try it, we won’t know how well that timing works. Earlier is likely better.

What do people affected by Fanconi anemia think of the prenatal treatment concept?

We recently published the first comprehensive assessment of people’s attitudes toward possible prenatal diagnosis and treatment for Fanconi anemia in the journal Prenatal Diagnosis. We surveyed 72 people who either have a Fanconi anemia diagnosis or have a child with Fanconi anemia. The participants were from 18 countries on five continents.

Generally, the people we surveyed showed really strong interest in prenatal diagnosis and treatment. Most participants—71% of all respondents and 100% of Fanconi anemia patients—said they would pursue prenatal diagnosis.

We asked how people would feel about prenatal stem cell transplant if it were FDA-approved: 91% of people with Fanconi anemia and 72% of parents of patients said they would likely pursue this option. We also asked about whether people would be open to participating in clinical trials of prenatal stem cell transplant, since trials are a critical part of understanding whether new treatments are safe and effective. We saw that 68% of our respondents would be open to participating in a clinical trial.

I think this shows that there is high receptivity to the idea of prenatal therapy. At the same time, our team recognizes that pursuing prenatal therapy is a personal choice, at a sensitive time in one’s life journey. That’s why we wanted to do this survey, to understand the perspectives of families who have a deep understanding of this disease.