Bitopertin improves erythropoiesis in the Rpl11-haploinsufficient mouse model of DBA. (A) Mice were fed chow containing 0, 30, 100, or 150 ppm for 8 weeks to identify the optimal dose of bitopertin. Changes in red cell complete blood count parameters relative to untreated mice are shown as mean ± standard deviation (SD) of 4 to 6 mice. Mice treated with 100 ppm bitopertin in chow (∼20 mg/kg per day) showed the best improvement. (B) Bitopertin levels in plasma were measured and shown for each treatment dose (top) or segregated by control and haploinsufficient mice (bottom). Plasma samples were collected 3 to 5 hours after light-on and generally reflect the nadir. Data from each mouse is shown individually along with the mean ± SD for each group. (C) Red cell complete blood count parameters of control and Rpl11-haploinsufficient mice treated and fed a controlled diet without and with 100 ppm bitopertin for 8 weeks. Data are presented as mean ± SD of 11 to 15 mice. Heme content (D) and cytoplasmic reactive oxygen species (E) in marrow erythroid precursors from control mice or Rpl11-haploinsufficient mice treated without or with 100 ppm bitopertin. Analysis was performed as before¹¹ and presented as the mean heme content ± SD (7-8 mice) or the mean fluorescence intensity of CM-DCFDA ± SD (4-6 mice) of at each stage of differentiation (I, colony-forming unit erythrocyte and proerythroblasts; II, basophilic erythroblasts; III, polychromatic erythroblasts; IV, orthochromatic erythroblasts and reticulocytes; V, retics and RBC). ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ns, P > .05. HCT, hematocrit; HGB, hemoglobin; MCV, mean corpuscular volume; ns, not significant; RBC, red blood cell; ROS, reactive oxygen species.