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Developmental biology - Stem Cell Trial Opens

Mom's stem cells may save her baby

A mother's blood stem cells transferred to her fetal child may cure her serious blood disorder...

Alpha thalassemia major (ATM) is almost universally fatal to a fetus. It is considered an 'orphan disease' with a need for effective therapies. The only current treatment is in utero transfusions (IUT) of red blood cells to treat fetal blood anemia (the red blood cells are unable to carry oxygen) and avoid the complications of hydrops, a life-threatening problem of severe swelling in the fetus or newborn, and death.

Often, ATM pregnancies undergo elective termination after a confirmed diagnosis. Those who receive In Utero Transfusions (IUT) and survive birth, ultimately require lifelong monthly blood transfusions or bone marrow transplant, if a suitable donor is available.

Now, there is a coming Phase 1 Clinical Trial: In Utero Hematopoietic Stem Cell Transplantation for Alpha-thalassemia Major (ATM). The trial is to demonstrate the safety, feasibility and efficacy of performing in utero stem cell transplants to ATM fetuses. Investigators are actively recruiting ten participants with prenatal diagnosis of ATM to undergo bone marrow harvest from their mothers and subsequent in utero transfusion back to the fetus of her maternal stem cells. Transplanting Hematopoietic Maternal stem Cells (HSC) into the fetus takes advantage of the existing fetal tolerance for maternal cells during pregnancy. The undeveloped fetal immune system is more tolerant of mother's transplanted blood cells without needing immunosuppression. Transfering a stem cell transplant at the same time as In Utero Transfusions (IUT) minimizes risk to the fetus.

Investigators also hope to demonstrate postnatal chimerism — meaning how a baby's body accepts cells from a matching donor, should a bone marrow transplant become necessary after delivery, as the baby is already conditioned to the new cells and immune suppression is not required.

Maternal stem cell transplant
Nichelle Obar gave birth on Feb. 1, 2018, to her daughter Elianna, after such a procedure. In the last three months before she was born, Elianna Constantino received five blood transfusions and a bone-marrow transplant — all from her mom. These transfusions were given with a needle passed through her mother’s abdomen and uterus, and into a vein in Elianna's umbilical cord. Elianna, was born crying robustly. Her condition alpha thalassemia major, generates red blood cells unable to carry oxygen which causes severe anemia, heart failure and brain damage to the infant. Her mother's transfusions kept her alive, but not cured. Though bone-marrow transplants have the potential to cure alpha thalassemia major, it is still too soon to tell whether it will succeed.

Elianna and her mother, Nichelle Obar, are the first patients in this clinical trial. If the IUT treatment continues to work for her and other families, it could open the door to using bone-marrow transplants before birth to cure not just Elianna’s ATM blood disease, but also sickle cell anemia, hemophilia and other hereditary blood disorders. Bone marrow teems with stem cells which can replace with healthy cells, cells that are missing or defective due to genetic flaws.
“This line of work moves the field of fetal surgery, which currently consists of big operations for anatomic disorders, in a new direction of molecular and cellular therapies given non-invasively.”

Tippi MacKenzie MD, Pediatric and Fetal Surgeon, Study Leader, U.C.S.F. Benioff Children’s Hospital,University of California, San Francisco, California, USA.

If a transplant is successful and the mother’s stem cells are incorporated into the baby’s own bone marrow, the baby will be able to make normal blood cells. If the transplant is not fully successful and blood cell engraftment is weak, a “booster” transplant of mom’s stem cells may be performed after delivery. Even low engraftment might result in a lasting tolerance of the mom’s blood cells, so a booster transplant can improve the baby's ability to make normal blood cells. A booster transplant is expected to be safer than the current method of stem cell transplant following birth.

Mothers who choose to participate in the clinical trial will have stem cells harvested from bone marrow in their hip bones. These cells will then be prepared for safe injection and transplantion into the fetus. The fetus will have additional blood transfusions before birth. The success of the cell transplant will be evaluated after birth. While the doctors believe in utero transplantation can be performed safely, it is possible that it may not be effective. Another potential risk of the procedure is that the fetus may become sick after the in utero transplantation — and may not survive the therapy. A mother may also need a blood transfusion herself, after donating bone marrow. In the event that in utero transplantation is not successful, repeated blood transfusions will be performed after birth and another stem cell transplant can be considered.

For more information visit the clinical trial information at ClinicalTrials.gov: In Utero Hematopoietic Stem Cell Transplantation for Alpha-thalassemia Major (ATM). You can also download a PDF brochure: Alpha Thalassemia Major Clinical Trial Brochure and read about favorable outcomes after in utero transfusion in fetuses with alpha thalassemia major.

Dr. MacKenzie and Dr. Vichinsky do not discourage parents who choose abortion. Dr. MacKenzie: “We are pro-choice. These are wanted pregnancies for whom therapy can be offered. You have a choice to terminate or you have a choice for therapy, but the bottom line is you have choice.”
Bone-marrow transplants in a fetus, sometimes are from the father, and were first tried in the 1990s. Some worked, but most failed, and doctors mostly abandoned the procedure, Dr. MacKenzie explains. But, as research continued in animals, a key finding emerged. The mother, not the fetus, was rejecting transplants that came from fathers or other donors. A possible solution became evident.

“Every fetus has a perfect donor, and that’s their mom.”
Tippi MacKenzie, MD

Genetically, a mother is not a complete match to the fetus as half of fetal genes come from the father. But mom is still the ideal donor before birth, as pregnancy allows the maternal and fetal immune systems to adapt to each other. Mother and child tolerate one another and so their cells do not fight and cause immune reactions. When the infant’s immune system starts to work independently in late pregnancy, this truce ends.

It may seem puzzling to give a fetus with a genetic disease stem cells from the mother who passed on the bad genes. But it can work. If the mother is a healthy carrier, her stem cells also have copies of the good genes that the child needs. People have two copies of nearly every gene, one copy from each parent. Alpha thalassemia major involves two genes, and two flawed copies of each of those genes.

Elianna in her first three months, like all children with her blood disorder, needs a transfusion every three weeks. But tests have found some of her mother’s stem cells in her blood. Whether they will start to help her is unknown. If they don't, her parents could eventually opt for a bone-marrow transplant in hopes of curing her disease and freeing her from a lifetime of blood transfusions. In that case, if some of her mother’s cells persist, they may make it possible for her to accept another transplant from Ms. Obar with less chemotherapy than that procedure usually requires.

Those decisions are a long way off. “Elianna’s doing great,” according to Ms. Obar. “I’m not disappointed at all. If it works, great. If it didn’t, we’re OK with it. We’ll celebrate all the little accomplishments. I’m glad we did it.”

This research was supported by the UC San Francisco California Preterm Birth Initiative, which is funded by Marc and Lynne Benioff. Additional support was provided by grants from the National Institute of Environmental Health Sciences (K99ES027023, P01ES022841, R01ES027051) and the U.S. Environmental Protection Agency (RD-83543301).

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Jun 5, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

Elianna (3 weeks) and her mother, Nichelle Obar, are the first patients to push the limits of
fetal therapy for ATM, through stem cell treatments in utero from mother to child.
Image credit: Bryan Meltz for The New York Times.

Phospholid by Wikipedia