Prenatal Transplantation for Fetuses With Fanconi Anemia

Agnieszka Czechowicz

Status and phase: Begins enrollment in 2 months; Phase 2; Phase 1

Conditions: Cancer Predisposition Syndrome; Fanconi Anemia; Bone Marrow Failure Disorders; Congenital Bone Marrow Failure Syndromes; Genetic Diseases, Inborn; Anemia, Hypoplastic, Congenital; DNA Repair-Deficiency Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Treatments: Biological: IUHSCT for FA-affected fetuses

Study type: Interventional

Funder types: Other

Identifiers

NCT07408583

84974

Details and patient eligibility

About

The investigators aim to evaluate the safety and efficacy of in utero hematopoietic stem cell transplantation (IUHSCT) for the treatment of fetuses diagnosed with Fanconi anemia (FA) during pregnancy.

Full description

Fanconi Anemia (FA) is a genetic disorder known to shorten the lifespans of those diagnosed due to inherited chromosomal fragility that leads to hematopoietic failure (cytopenia, aplastic anemia, myelodysplasia, or leukemia), increased cancer risk, and other possible rare organ dysfunction such as congenital structural anomalies. Importantly, 80-90% of FA patients develop bone marrow failure (BMF) by 12 years of age.

This is a phase I/II clinical trial to investigate the safety and efficacy of performing in utero hematopoietic stem cell transplantation (IUHSCT) for fetuses diagnosed with FA during pregnancy. The investigators aim to recruit twelve participants with a prenatal diagnosis of FA. Participants will undergo bone marrow harvest followed by an ultrasound guided in utero infusion of maternal stem cells. Transplanting maternal cells into the fetus takes advantage of the immature fetal immune system and existing maternal-fetal tolerance during pregnancy to enable stem transplantation without use of any conditioning or immunosuppression.

The investigators intend to demonstrate that it is safe and effective to perform IUHSCT in fetuses diagnosed with FA. Additionally, the investigators want to demonstrate postnatal chimerism of maternal cells and correction of the DNA-repair deficiency in the blood and bone marrow. This procedure hopes to prevent the need for a future bone marrow transplant later in life, or if one remains necessary then it hopes that conditioning and immune suppression will not be required when using maternal stem cells due to persistant maternal tolerance.

Enrollment: 12 estimated patients

Sex: All

Volunteers: No Healthy Volunteers

Inclusion criteria

• Male or female fetuses from 19^0/7 - 28^0/7 weeks gestational age at time of transplant.
• Diagnosed with FA by either chorionic villus sampling (CVS), or amniocentesis, or cordocentesis with abnormal fetal chromosomal breakage studies and/or FANC gene mutations when combined with at least one of the following: 1) abnormal chromosomal breakage result consistent with an FA diagnosis, 2) family history of a 1st degree relative with confirmed FA, or 3) congenital anomalies consistent with the diagnosis of FA on fetal ultrasound.
• 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 Participant Exclusion Criteria: Major anatomic or genetic anomalies that contributes a significant morbidity or mortality risk, and/or echocardiogram or ultrasound findings that indicate a high risk of fetal demise after fetal intervention. Fetuses with a normal chromosomal breakage study that determines they are likely FA negative.
• 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 a body mass index greater than 40, significant maternal cardiac disease, mirror syndrome, clinically symptomatic maternal anemia, Preterm premature rupture of membranes (PPROM), Active Preterm labor (PTL), opioid use disorder, current use of anticoagulants.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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12 participants in 1 patient group

Intervention - in utero hematopoietic stem cell transplantation

Experimental group

Description:

Single dose in utero hematopoietic stem cell transplantation (IUHSCT) in fetuses with Fanconi anemia during 19 - 28 weeks gestation. The cellular product is: Semi-allogeneic, Related, Maternal Bone Marrow-Derived, Miltenyi CliniMACS Plus enriched CD34+ hematopoietic stem cells administered in utero at a dose of 1 x 10\^7-10\^9 cells/kg fetal weight with equal to or less than 1% CD3+ T cells (equivalent to 10\^5-10\^7 T cells/kg fetal weight) in a final volume of 2-5ml suspended in 5% human serum albumin in Normosol buffer (Hospira, Inc.).

Treatment:

Biological: IUHSCT for FA-affected fetuses