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

Diamond-Blackfan anemia (DBA) results from germ line haploinsufficiency of 1 of at least 26 distinct ribosomal proteins. Although patients with DBA have hematopoietic stem and progenitor cell defects, the dominant clinical phenotype is severe anemia. In ~60% of patients with DBA, 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, whereas the production of heme, which requires a small amount of protein because it is synthesized enzymatically, proceeds at a near normal rate. This results in an excess of intracellular heme in early erythroblasts, elevated reactive oxygen species, 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 3 studies. We reasoned that bitopertin might help balance heme synthesis with globin synthesis and improve erythropoiesis in patients with DBA. Our observations in samples from patients with DBA, CD34+ cells engineered to downregulate RPS19, and a murine DBA model support this concept, justify ongoing clinical studies, and provide insight into optimal trial design.