Luspatercept

Beta thalassemia is a genetic red blood cell disorder caused by mutations in the β-globin gene - these mutations cause oxidative stress and premature apoptosis of erythroblasts, thereby leading to ineffective erythropoesis. The transforming growth factor beta (TGF-β) superfamily of endogenous ligands (including activins, growth differentiation factors, and bone morphogenetic proteins) are involved in the inhibition of erythroid differentiation via activation of the Smad2/3 subfamily of intracellular effectors.

Luspatercept is a fusion protein comprising a modified extracellular domain of activin receptor type IIB (a target for many TGF-β ligands) fused to the FC domain of human IgG1. Luspatercept ameliorates ineffective erythropoiesis in patients with beta thalassemia by acting as a "ligand trap" for various members of the TGF-β superfamily, preventing their downstream signalling and subsequent inhibition of late-stage erythroid maturation. The specific members of the TGF-β superfamily targeted by luspatercept are currently unknown, though growth differentiation factor 11 (GDF11) has been experimentally excluded as a potential target.