In utero hematopoietic stem cell transplantation for Fanconi anemia.

Advances in prenatal diagnostic tools have enabled early diagnosis of many inherited diseases. Suspicion for FA in a developing fetus often arises based upon family history and/or detection of congenital abnormalities on ultrasound.13 Subsequently, FA can be verified by genetic sequencing and/or chromosomal breakage testing on fetal cells obtained by chorionic villus sampling or amniocentesis. Such diagnostic tests can be performed as early as 10-weeks’ gestation,13 before the optimal timing for IUHSCT.14 IUHSCT is most commonly conducted by transplantation of HSCs derived from donor bone marrow (BM) into the fetus through the umbilical vein via ultrasound guidance, and has been successfully performed in preclinical and clinical studies for immunodeficiencies and hemoglobinopathies without genotoxic myeloablation or immunosuppression.14,15 Despite high technical success and safety, clinical application of IUHSCT has been challenged to date due to limited engraftment below therapeutic levels for most diseases. This is likely due to donor HSC competition with the fetus’ HSCs, which cannot be overcome without HSC-ablative conditioning.16 However, in FA, we have shown that only minimal initial donor cell engraftment is necessary to stabilize the failing BM environment due to the competitive advantage of healthy cells over failing FA cells.8,17 Given this, we hypothesized that IUHSCT could stabilize the FA hematopoietic system without conventional postnatal HSCT toxicities, providing an alternative attractive early treatment option for patients with FA regardless of genotype. Specifically, IUHSCT could be a safer and easier option to prevent hematologic disease without the common complications of postnatal HSCT, including infections, mucositis, GVHD, infertility, secondary malignancies, and prolonged hospitalization/immune compromise.