Decrease in α-Globin and Increase in the Autophagy-Activating Kinase ULK1 mRNA in Erythroid Precursors from...

Area of Science:

• Hematology
• Molecular Biology
• Genetics

Background:

• Beta-thalassemia is a genetic disorder causing low adult hemoglobin and toxic excess alpha-globin, leading to ineffective erythropoiesis.
• Reducing excess alpha-globin is a key therapeutic goal, achievable via fetal hemoglobin induction or autophagy.
• Sirolimus (rapamycin) and its analogs show potential for inducing fetal hemoglobin (HbF) in hemoglobinopathies.

Purpose of the Study:

• To investigate the effects of sirolimus on autophagy, ULK-1 expression, and alpha-globin reduction in erythroid precursors.
• To evaluate sirolimus's impact on these markers in erythroid precursors from beta-thalassemia patients in a clinical trial.

Main Methods:

• In vitro stimulation of erythroid precursors (ErPCs) with low-dose sirolimus.
• Analysis of autophagy markers (p62), ULK-1 expression (protein and mRNA), and alpha-globin content.
• Isolation and analysis of ErPCs from beta-thalassemia patients treated in the NCT03877809 clinical trial.

Main Results:

• Low-dose sirolimus in vitro decreased p62, increased ULK-1 expression, and reduced excess alpha-globin in ErPCs.
• ErPCs from sirolimus-treated patients showed increased ULK-1 mRNA and decreased alpha-globin.
• These findings indicate sirolimus influences key pathways relevant to beta-thalassemia.

Conclusions:

• Sirolimus treatment is associated with reduced excess alpha-globin in beta-thalassemia.
• Autophagy and ULK-1 expression are potential biomarkers for sirolimus efficacy.
• These cellular mechanisms and markers should be considered in sirolimus-based clinical trials for beta-thalassemia.