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Bitopertin, a selective oral GLYT1 inhibitor, improves anemia in a mouse model of β-thalassemia
Alessandro Matte, … , Carlo Brugnara, Lucia De Franceschi
Alessandro Matte, … , Carlo Brugnara, Lucia De Franceschi
Published October 8, 2019
Citation Information: JCI Insight. 2019;4(22):e130111. https://doi.org/10.1172/jci.insight.130111.
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Research Article Hematology

Bitopertin, a selective oral GLYT1 inhibitor, improves anemia in a mouse model of β-thalassemia

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Abstract

Anemia of β-thalassemia is caused by ineffective erythropoiesis and reduced red cell survival. Several lines of evidence indicate that iron/heme restriction is a potential therapeutic strategy for the disease. Glycine is a key initial substrate for heme and globin synthesis. We provide evidence that bitopertin, a glycine transport inhibitor administered orally, improves anemia, reduces hemolysis, diminishes ineffective erythropoiesis, and increases red cell survival in a mouse model of β-thalassemia (Hbbth3/+ mice). Bitopertin ameliorates erythroid oxidant damage, as indicated by a reduction in membrane-associated free α-globin chain aggregates, in reactive oxygen species cellular content, in membrane-bound hemichromes, and in heme-regulated inhibitor activation and eIF2α phosphorylation. The improvement of β-thalassemic ineffective erythropoiesis is associated with diminished mTOR activation and Rab5, Lamp1, and p62 accumulation, indicating an improved autophagy. Bitopertin also upregulates liver hepcidin and diminishes liver iron overload. The hematologic improvements achieved by bitopertin are blunted by the concomitant administration of the iron chelator deferiprone, suggesting that an excessive restriction of iron availability might negate the beneficial effects of bitopertin. These data provide important and clinically relevant insights into glycine restriction and reduced heme synthesis strategies for the treatment of β-thalassemia.

Authors

Alessandro Matte, Enrica Federti, Michael Winter, Annette Koerner, Anja Harmeier, Norman Mazer, Tomas Tomka, Maria Luisa Di Paolo, Luigia De Falco, Immacolata Andolfo, Elisabetta Beneduce, Achille Iolascon, Alejandra Macias-Garcia, Jane-Jane Chen, Anne Janin, Christhophe Lebouef, Franco Turrini, Carlo Brugnara, Lucia De Franceschi

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Figure 4

Bitopertin treatment modulates HRI activity and improves autophagy, resulting in optimization of the quality control process with amelioration of red cell survival.

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Bitopertin treatment modulates HRI activity and improves autophagy, resu...
(A) Wb analysis of HRI phosphorylation and eIF2αP levels in sorted 1.5 × 106 CD44+Ter119+FSChi spleen cells from Hbbth3/+ mice with and without bitopertin treatment (10 mg/kg/d, 28 days) (n = 3). (B) Left: Wb analysis of phospho-mTOR (p-mTOR), mTOR, Rab5, Lamp1, and p62 in reticulocyte-enriched fractions from WT and Hbbth3/+ mice with and without bitopertin treatment (n = 3; 10 mg/kg/d, 28 days). Catalase was used as a protein loading control. Right: Densitometric analyses of the immunoblot bands similar to those shown are presented. Data are shown as median and minimum/maximum (n = 4); *P < 0.05 compared with WT; °P < 0.05 compared with vehicle; 2-way ANOVA with Holm-Šídák test for multiple comparisons. (C) Hemichromes bound to the membrane in WT and Hbbth3/+ mice with and without bitopertin treatment (n = 3; 10 mg/kg/d, 28 days). Data are shown as median and minimum/maximum (n = 4); P < 0.05 compared with WT; °P < 0.05 compared with vehicle; 2-way ANOVA with Holm-Šídák test for multiple comparisons. (D) ROS levels in red cells of WT and Hbbth3/+ mice with and without bitopertin treatment (10 mg/kg/d, 28 days). Data are presented as median and minimum/maximum (n = 6); *P < 0.05 compared with vehicle-treated Hbbth3/+mice; °P <0.05 compared with vehicle. 2-way ANOVA with Holm-Šídák test for multiple comparisons. (E) Wb analysis of thioredoxin-reductase (Trx-R) and peroxiredoxin-2 (Prx2) in erythrocytes from WT and Hbbth3/+ mice with and without bitopertin treatment (n = 3; 10 mg/kg/d, 28 days). Catalase was used as a protein loading control (see Supplemental Figure 6, A and B, for densitometric analyses). (F) Red cell survival of CFSE-labeled red cells from WT and Hbbth3/+ mice with and without bitopertin treatment (n = 3; 10 mg/kg/d, 40 days). Data are presented as mean ± SD (n = 3) from each group; *P < 0.05 compared with WT; °P < 0.05 compared with vehicle; Wilcoxon’s signed-rank test for multiple comparisons.

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