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

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 25 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).