@article{10.1172/jci.insight.130111, author = {Alessandro Matte AND Enrica Federti AND Michael Winter AND Annette Koerner AND Anja Harmeier AND Norman Mazer AND Tomas Tomka AND Maria Luisa Di Paolo AND Luigia De Falco AND Immacolata Andolfo AND Elisabetta Beneduce AND Achille Iolascon AND Alejandra Macias-Garcia AND Jane-Jane Chen AND Anne Janin AND Christhophe Lebouef AND Franco Turrini AND Carlo Brugnara AND Lucia De Franceschi}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Bitopertin, a selective oral GLYT1 inhibitor, improves anemia in a mouse model of β-thalassemia}, year = {2020}, month = {3}, volume = {4}, url = {https://insight.jci.org/articles/view/130111}, 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.}, number = {22}, doi = {10.1172/jci.insight.130111}, url = {https://doi.org/10.1172/jci.insight.130111}, }