Prenatal Transplantation for Fetuses With Fanconi Anemia

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.

• IUHSCT for FA-affected fetuses (Biological): Single-dose IUHSCT Administration of Semi-allogeneic, Related, Maternal Bone Marrow-Derived, Miltenyi CliniMACS Plus Enriched CD34+ Hematopoietic Stem Cells Administered in Utero via fetal injection during 19 - 28 weeks gestation.

Primary outcomes

• Number of Maternal Participants with Treatment-Emergent Adverse Events (TEAEs) as Assessed by CTCAE v6.0. [From day of treatment to final maternal study visit (30 +/- 15 days after delivery).]: Number of maternal participants with treatment-emergent adverse events (TEAEs) as assessed by CTCAE v6.0.
• Number of Maternal Participants with Serious Adverse Events (SAEs) as Assessed by CTCAE v6.0. [From day of treatment to final maternal study visit (30 +/- 15 days after delivery).]: Number of maternal participants with serious adverse events (SAEs) as assessed by CTCAE v6.0.
• Number of Fetal Participants with Treatment-Emergent Adverse Events (TEAEs) as Assessed by CTCAE v6.0. [From day of treatment to child's final study visit (24 months after birth).]: Number of fetal participants with treatment-emergent adverse events (TEAEs) as assessed by CTCAE v6.0.
• Number of Fetal Participants with Serious Adverse Events (SAEs) as Assessed by CTCAE v6.0. [From day of treatment to child's final study visit (24 months after birth).]: Number of fetal participants with serious adverse events (SAEs) as assessed by CTCAE v6.0.

Sex: All

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.

• Swartzrock L, Dib C, Denis M, Willner H, Ho K, Haslett E, Han J, Pan W, Byrne-Steele M, Brown B, Krampf MR, Girsen A, Blumenfeld YJ, El-Sayed YY, Roncarolo MG, MacKenzie TC, Czechowicz AD. In utero hematopoietic stem cell transplantation for Fanconi anemia. Blood Adv. 2024 Sep 10;8(17):4554-4558. doi: 10.1182/bloodadvances.2023011894. No abstract available. PMID 38991119
• Dave A, Liu S, Riley JS, Bose S, Luks V, Berkowitz C, Menon P, Jung S, Li H, Kurre P, Peranteau WH. In utero hematopoietic cell transplantation leads to sustained engraftment in a mouse model of Fanconi anemia. Blood Adv. 2024 Feb 13;8(3):624-628. doi: 10.1182/bloodadvances.2023010354. No abstract available. PMID 37906519
• Lum T, Lee C, MacKenzie T, Lianoglou B, Czechowicz A. Attitudes Toward Prenatal Interventions in the Fanconi Anemia Community. Prenat Diagn. 2026 Feb 19. doi: 10.1002/pd.70077. Online ahead of print. PMID 41711672

• Yair Blumenfeld, MD, Principal investigator, Stanford University
• Tippi MacKenzie, MD, Principal investigator, University of California, San Francisco