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Minihepcidins to treat ß-thalassemia major mice
decreased in the minihepcidin-treated Hbbth1/th2BMC mice. Interestingly, serum erythroferrone levels were decreased, as expected by a reduction in the number of erythroid progenitor cells, while hepcidin level was reduced in comparison to that in untreated mice. This could be explained by the reduction in liver iron concen- tration, which may prevail over reduced erythroferrone levels on regulating hepcidin expression. When a mini- hepcidin was combined with transfusion, it further improved splenomegaly, with animals treated in this way showing an average spleen weight similar to that of WT mice. This suggests that, in TDT patients, this approach could further prevent or decrease splenomegaly, thereby reducing the requirement for splenectomy.
Interestingly, in this setting (6 weeks of weekly blood transfusions), we did not observe any effect of the mini- hepcidin on anemia (seen 6 days after the last blood trans- fusion). It is possible that our transfusion regimen (rate of administration, 6-week treatment and volume of blood transfused) may have been insufficient to show potential differences associated with the administration of minihep- icidins. Alternatively, administration of the minihepicidin may have slightly reduced the life-span of transfused RBC (Online Supplementary Figure S8). Future studies will address whether this phenomenon is associated only with this compound or with any drug that activates or mimics hep- cidin activity. Looking at the characteristics of this mouse model, different endpoints may be observed in ß-tha- lassemic patients treated with a similar drug. For instance these animals appear to absorb more iron and produce more reticulocytes compared to humans. In addition, the amount of transfusion was limited (only 6 weeks com- pared to lifelong treatment in humans) and the regimen of drug administration will likely be different in young and old patients. Nevertheless, our data indicate that minihep- icidin administration provides several beneficial effects in
combination with transfusion, such as reducing serum and heart iron concentration, while improving ineffective ery- thropoiesis, and splenomegaly. Based on previous data from thalassemia intermedia mice and now from this new TDT model, we speculate that administration of minihep- icidins may reduce or eliminate the requirement for trans- fusions by enhancing the efficiency of endogenous, more iron-restricted, erythropoiesis in several scenarios: (i) for those NTDT patients who become progressively more transfusion-dependent due to disease progression and (ii) in patients with intermittent transfusion requirements, sta- bilizing endogenous hemoglobin synthesis sufficiently to avoid transfusion.4,5,45,46 These potentially beneficial effects of minihepicidins may be further enhanced by combina- tion with drugs that increase RBC synthesis, such as luspa- tercept or sotatercept.47-50
In conclusion, we generated a new model of TDT that can be utilized to test drugs with the potential to improve ineffective erythropoiesis and anemia. Furthermore, we demonstrate that a minihepicidin has the potential to improve erythropoiesis and iron metabolism in this model, providing pre-clinical proof-of-concept for its use also in β-thalassemic patients affected by forms of ane- mias more severe than those observed in NTDT.
Acknowledgments
This work was supported by Merganser Biotech and grants from the National Institute of Diabetes and Digestive and Kidney Diseases and National Heart, Lung, and Blood Institute of the National Institutes of Health: R01 DK090554 (to SR), R01 DK095112 (to RF, SR, and YZG), R01 DK107670 (to YZG). Complete blood count were analyzed by the Translational Core Laboratory of the CHOP Research Institute and the Institutional Clinical and Translational Science Award Research Center, National Center for Advancing Translational Sciences (NIH/NCATS) grant UL1TR000003.
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