In Utero Hematopoietic Stem Cell Transplantation for Alpha-thalassemia Major (ATM)

A Single-Center, Non-Randomized Study of the Safety and Efficacy of In Utero Hematopoietic Stem Cell Transplantation for the Treatment of Fetuses With Alpha Thalassemia Major

The investigators aims to evaluate the safety of in utero hematopoietic stem cell transplantation in fetuses with alpha-thalassemia major performed at the time of in utero transfusion of red blood cells.

Alpha thalassemia major (ATM) is almost universally fatal in utero and represents an orphan disease with an unmet need for effective therapies. The only current treatment to allow the fetus to be born is to perform in utero transfusions (IUT) of red blood cells to treat the anemia and avoid the complications of hydrops and fetal demise. Often, affected pregnancies undergo elective termination after diagnosis. Cases with prenatal diagnosis of ATM who receive IUT and survive to birth will ultimately require lifelong monthly blood transfusions or bone marrow transplant, if a suitable donor is identified.

This is a phase 1 clinical trial to demonstrate the safety, feasibility and efficacy of performing in utero stem cell transplantation on fetuses affected with ATM. The investigators aim to recruit ten participants with a prenatal diagnosis of ATM. Participants will undergo bone marrow harvest and an in utero transfusion combined with maternal stem cells. Transplanting maternal cells into the fetus takes advantage of existing maternal-fetal tolerance during pregnancy. Hematopoietic stem cell (HSC) transplantation into the fetus takes advantage of the developing fetal immune system to induce tolerance to the transplanted cells without using conditioning or immunosuppression. Performing stem cell transplantation at the same time as IUT minimizes any additional procedural risk to the fetus.

The investigators hope to demonstrate that it is safe and feasible to perform in utero stem cell transplantation. Additionally, the investigators want to demonstrate postnatal chimerism of maternal cells so that, if a bone marrow transplant remains necessary after delivery, conditioning and immune suppression will not be required.

Inclusion Criteria:

• Male or female fetuses from 18 weeks and 0/7 days to 26 weeks 0/7 days gestation with a diagnosis of alpha-thalassemia major by chorionic villus sampling (CVS), amniocentesis, cordocentesis or by identification of parents as genetic carriers, and identification of fetal anemia or signs of impending hydrops, for whom parents elect to pursue in utero transfusion, and are willing to undergo subsequent IUT for the remainder of gestation.
• parents must consent to fetal autopsy in the event of a fetal demise
• adequate bone marrow harvest from maternal participant is a condition for inclusion

Exclusion Criteria:

• Fetal Subject Exclusion Criteria: Fetal participants will be excluded if they have a second major anatomic anomaly (not related to the underlying thalassemia) that contributes a significant morbidity or mortality risk, or echocardiogram or ultrasound findings that indicate a high risk of fetal demise after fetal intervention.
• Maternal Subject Exclusion Criteria: Maternal participants will be excluded if they have one or more morbidities that would preclude bone marrow harvest and fetal intervention including, but not limited to, morbid obesity with BMI > 35, maternal cardiac disease, mirror syndrome, symptomatic maternal anemia, or if they develop preterm premature rupture of membranes (PPROM) or active preterm labor (PTL).