Treatment with salubrinal increases the number of erythrocytes expressing fetal hemoglobin in a mouse model of sickle cell disease (SCD), according to a new study published in PLOS One. It also decreases the number of sickle-shaped erythrocytes. These findings support the possible role of salubrinal as an inducer of fetal hemoglobin and suggest that it could potentially be used as a therapy for SCD.
In SCD, a mutation in the HBB gene causes the formation of so-called S hemoglobin. S-hemoglobin molecules polymerize under low-oxygen conditions resulting in vaso-occlusive crises, chronic hemolysis, and progressive organ damage.
Inducing the production of fetal hemoglobin has been proposed as a therapeutic approach for SCD. Hydroxyurea is one such pharmacological agent and the only one approved by the US Food and Drug Administration.
Here, a team of researchers led by Betty S. Pace, MD, from the Department of Biochemistry and Cancer Biology, Augusta University in Georgia evaluated whether salubrinal could also induce the production of fetal hemoglobin.
Read more about the pathophysiology of SCD
The researchers treated erythroid progenitor cells with 24μM of salubrinal and found that this led to a 1.4-fold increase in cells expressing fetal hemoglobin. It also resulted in an 80% decrease in reactive oxygen species.
Using Western blot analysis, the researchers showed that salubrinal treatment resulted in a 1.6-fold increase in fetal hemoglobin production. There was also a dose-dependent increase in the levels of p-eIF2α and ATF4 levels.
Finally, the researchers treated mice with SCD with salubrinal at a dose of 5 mg/kg and found that this led to a 2.3-fold increase in erythrocyte expressing fetal hemoglobin.
Salubrinal is a selective protein phosphatase 1 inhibitor, which induces the expression of fetal hemoglobin through the stress-signaling pathway through the activation of p-eIF2α and ATF4 in the promoter of the genes encoding γ-globin.
Lopez NH, Li B, Palani C, et al. Salubrinal induces fetal hemoglobin expression via the stress-signaling pathway in human sickle erythroid progenitors and sickle cell disease mice. PLOS One. 2022;17(5):e0261799. doi:10.1371/journal.pone.0261799