The importance of identifying further pathways that are associated with HbF levels regulation in patients with SCD

The article by Zhang et al. (2016) is guided by an increased need for fetal hemoglobin (HbF)-inducing drugs since only half of the patients benefit from the only US Food and Drug Administration–approved drug for the management of sickle cell disease (SCD), hydroxyurea (HU). Approximately 50% of the patients taking HU have minimal clinical improvement, with research still ongoing on the genetic factors that influence response to HU. This creates the importance of identifying further pathways that are associated with HbF levels regulation in patients with SCD. FOXO3 is a novel gene that regulates the expression of ỳ-globin positively with some of its roles, including antioxidant response, longevity, and cell cycle control. FOXO3 knockdown arrests erythroid maturation, and its activation promotes erythroid maturation. Metformin, a drug used in the treatment of diabetes, has been shown to activate FOXO3; hence the article summarizes the role of FOXO3 in ỳ -globin gene regulation through the expression of lentiviral, RNA interference, and metformin induction.

For the study, 171 pediatric patients with SCD and not on HU underwent whole-exome sequencing (WES), including HbSS and HbSβ ο . The study's findings established that FOXO3 is a candidate gene involved in the regulation of RBC HbF. SCD severity is significantly modified by HbF levels. The study's findings show that individuals with nonsynonymous variants in FOXO3 had lower levels of HbF. The study also found out that metformin increases FOXO3 expression and causes the accumulation of this gene in the nucleus. The study aimed at establishing whether an increase in FOXO3 in the nucleus through drug induction could increase HbF. The mechanism of action of metformin differs from the HU mechanism of action since contrary to HU, which induces HbF through increasing stress erythropoiesis, metformin through FOXO3, helps in the management of oxidative stress in erythroid cells. Metformin, therefore, works through metabolic manipulation. The study concludes that metformin is an assuring HbF-inducing agent that can potentially meet the clinical needs of some SCD patients (Zhang et al., 2016).

References 

Zhang, Y., Weiss, M., Sumazin, P., & Sheehan, V. A. (2016). Metformin Induces FOXO3-Dependent Fetal Hemoglobin Production in Primary Erythroid Cells.  Blood ,  128 (22), 322–322. https://doi.org/10.1182/blood.v128.22.322.322