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. 2024 Sep 10;8(17):4554-4558.
doi: 10.1182/bloodadvances.2023011894.

In utero hematopoietic stem cell transplantation for Fanconi anemia

Leah Swartzrock  1   2   3 , Carla Dib  1   2   3 , Morgane Denis  1   2   3 , Hana Willner  1   2   3 , Katie Ho  1   2   3 , Ethan Haslett  1   2   3 , Jian Han  4 , Wenjing Pan  4 , Miranda Byrne-Steele  4 , Brittany Brown  4 , Mark R Krampf  1   2   3 , Anna Girsen  5   6 , Yair J Blumenfeld  5   6 , Yasser Y El-Sayed  5   6 , Maria G Roncarolo  1   2   3 , Tippi C MacKenzie  7   8 , Agnieszka D Czechowicz  1   2   3
Affiliations

In utero hematopoietic stem cell transplantation for Fanconi anemia

Leah Swartzrock et al. Blood Adv. .
No abstract available

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Conflict of interest statement

Conflict-of-interest disclosure: A.D.C. discloses financial interests in the following entities working in the rare genetic disease space: Beam Therapeutics, Editas Medicine, GV, Inograft Biotherapeutics, Magenta Therapeutics, Prime Medicine, and Spotlight Therapeutics. M.G.R. is a cofounder and has equity in Tr1X Inc and serves on the board of directors of Atara Biotherapeutics and Cosmo Pharmaceuticals and receives compensation for those activities. T.C.M. has received grant funding from companies in the rare disease space, including Novartis, BioMarin, Biogen, and Ultragenyx. The remaining authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
IUHSCT allows for robust donor engraftment in homozygous Fancd2–/– mice with WT competitive advantage over time. (A) Generation of Fancd2–/–, Fancd2+/−, and WT fetuses and in utero transplantation schema. Parental FA carriers (Fancd2+/− CD45.2) were mated to generate time-dated FA fetuses. BM from WT (CD45.1) mice was isolated and CD117 enriched by magnetic separation. At E13.5-14.5, fetuses were transplanted via intrahepatic injection with 1 × 106 CD117+ selected HSCs. Pups were genotyped and subsequently monitored (WT, n = 5; Fancd2+/−, n = 10; and Fancd2–/–, n = 3). Peripheral blood and BM donor chimerism was assessed by flow cytometry (% CD45.1) at various time points after IUHSCT. Multilineage donor chimerism was examined in (B) granulocytes and (C) lymphocytes, including B cells, CD4 helper T cells, and CD8 cytotoxic T cells. (D) LT-HSC chimerism was also measured. (E) HSC and progenitor functionality and resistance to DNA damaging agent mitomycin C was further assessed by CFU assays (n = 3) and (F) secondary transplantation in lethally irradiated WT mice (n = 4). Data represent mean ± standard error of the mean (SEM). Comparisons were performed using analysis of variance (ANOVA) with Tukey multiple comparison test, and a P value of <.05 was considered significant. ∗∗∗∗P < .0001; ∗∗∗P < .001; ∗∗P < .01; ∗P < .05. CFU, colony-forming unit; ns, nonsignificant.
Figure 2.
Figure 2.
IUHSCT similarly allows for robust donor engraftment in homozygous Fanca–/– mice with WT competitive advantage over time.Fanca–/–, Fanca+/−, and WT fetuses were generated as previously described for Fancd2–/– mice. At E13.5-14.5, fetuses were transplanted via intrahepatic injection with 1 × 106 CD117+ selected HSCs. Pups were genotyped and followed (WT, n = 2; Fanca+/−, n = 4; and Fanca–/–, n = 2). Peripheral blood and BM donor chimerism was assessed by flow cytometry (% CD45.1) at various time points after IUHSCT. (A) Multilineage donor chimerism was examined in (A) granulocytes and (B) lymphocytes, including B cells, CD4 helper T cells, and CD8 cytotoxic T cells. (C) LT-HSC chimerism was also determined. Data represent mean ± SEM. Comparisons were performed using ANOVA with Tukey multiple comparison test, and a P value of <.05 was considered significant. ∗∗∗∗P < .0001; ∗∗∗P < .001; ∗∗P < .01; ∗P < .05. ns, nonsignificant.
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