Session: 112. Thalassemia and Globin Gene Regulation: Poster I
Hematology Disease Topics & Pathways:
Research, Translational Research, Thalassemia, Hemoglobinopathies, hematopoiesis, Diseases, Biological Processes
To establish the proper dose regimen with withdrawal periods for prolonged cFGF23 treatment, we analyzed bone mineral density (BMD) and HSC cell cycle at 1 and 2 weeks after discontinuing cFGF23 administration. Our results showed that rescued BMD was sustained after the discontinuation of treatment for 1 and 2 weeks (th3 vs. th3+cFGF23 _1wk vs. th3+cFGF23_2wks: 125.9±3.8 vs. 181±19.9 vs. 142±1.6 mg/cm3, p<0.01). Ongoing histomorphometric analysis will provide a better characterization of bone quality. Additionally, we observed the restoration of defective quiescence in th3 HSCs after 1- and 2 weeks (th3 vs. th3+cFGF23 _1wk vs. th3+cFGF23_2wks: 77.8±1,4 vs. 92.1±1.8 vs. 87.8±0.9 on Linneg BM cells, p<0.001).
To test autologous transplantation upon gene therapy, we transduced th3 Linneg BM cells with a lentiviral vector carrying the β-globin gene (GLOBE LV) at MOI 5 resulted in a mean vector copy number of 1 and a transduction efficiency of 50%. We performed competitive transplantation using 1x105 (CD45.1) transduced donor th3 cells and 1x105 (CD45.2) competitor mock-transduced th3 cells into busulfan-conditioned (CD45.2) untreated th3 or th3+cFGF23 recipient mice. The treated recipient mice received two doses of cFGF23 every 2 weeks as a maintenance regimen. We observed higher engraftment of transduced cells in the peripheral blood of cFGF23-treated mice at 8 weeks post-transplant (th3 vs. th3+cFGF23: 4.9±1.1 vs. 10.7±1.9 % of CD45.1 engrafted cells, p<0.05). Comparative evaluation of hematological parameters and molecular analysis of transduced cells are ongoing.
Targeting FGF23 signaling provides a promising strategy to improve bone defects and HSC-niche alterations in βThal. Here, we show that the use of FGF23 inhibition in the transplantation setting in β-thalassemia results in superior engraftment of donor cells in treated recipients, indicating a potential application to ameliorate the clinical outcome.
Disclosures: No relevant conflicts of interest to declare.
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