Decrease in -Globin and Increase in the Autophagy-Activating Kinase ULK1 mRNA in Erythroid Precursors from -Thalassemia Patients Treated with Sirolimus

The beta-thalassemias are hereditary monogenic diseases characterized by a low or absent production of adult hemoglobin and excess in the content of alpha-globin. This excess is cytotoxic for the erythroid cells and responsible for the beta-thalassemia-associated ineffective erythropoiesis. Therefore, the decrease in excess alpha-globin is a relevant clinical effect for these patients and can be realized through the induction of fetal hemoglobin, autophagy, or both. The in vivo effects of sirolimus (rapamycin) and analogs on the induction of fetal hemoglobin (HbF) are of key importance for therapeutic protocols in a variety of hemoglobinopathies, including beta-thalassemias. In this research communication, we report data showing that a decrease in autophagy-associated p62 protein, increased expression of ULK-1, and reduction in excess alpha-globin are occurring in erythroid precursors (ErPCs) stimulated in vitro with low dosages of sirolimus. In addition, increased ULK-1 mRNA content and a decrease in alpha-globin content were found in ErPCs isolated from beta-thalassemia patients recruited for the NCT03877809 clinical trial and treated with 0.5-2 mg/day sirolimus. Our data support the concept that autophagy, ULK1 expression, and alpha-globin chain reduction should be considered important endpoints in sirolimus-based clinical trials for beta-thalassemias.