Restricting glycine uptake with bitopertin improves erythropoiesis in preclinical models of Diamond-Blackfan anemia

• Bitopertin reduces heme synthesis, increases the erythroid differentiation of DBA cells in vitro, and improves anemia in a murine DBA model. • The data justify a trial of bitopertin in DBA patients and suggest a lower dose than used in prior unrelated trials could be efficacious. Diamond-Blackfan anemia (DBA) results from germline haploinsufficiency of one of at least 26 distinct ribosomal proteins. While DBA patients have hematopoietic stem/progenitor cell defects, the dominant clinical phenotype is severe anemia. In ∼60% of DBA patients, the anemia responds to corticosteroids. However, these responses are often time-limited and steroid-related complications are common, leaving an unmet need for an effective and safe oral therapy. In DBA, ribosomal haploinsufficiency leads to slowed translation and impaired protein synthesis. Globin synthesis is significantly slowed, while the production of heme, which requires a small amount of protein since it is synthesized enzymatically, proceeds at a near normal rate. This results in an excess of intracellular heme in early erythroblasts, elevated ROS, and other heme-induced toxicity. Bitopertin, an oral competitive inhibitor of glycine import, has been shown to reduce heme synthesis and to have an excellent safety profile in unrelated phase 2 and phase 3 studies. We reasoned that bitopertin might help balance heme synthesis with globin synthesis and improve erythropoiesis in DBA patients. Our observations in DBA patient samples, CD34+ cells engineered to down-regulate RPS19, and a murine DBA model support this concept, justify ongoing clinical studies, and provide insight into optimal trial design.