Unlocking Fetal Hemoglobin Potential: The Therapeutic Role of ML-0207/ASP8731 in Sickle Cell Disease Management

Sickle cell disease (SCD) is a genetic disorder caused by a mutation in the β-globin gene, leading to the production of hemoglobin S (HbS). Deoxygenated red blood cells with HbS can form polymers that trigger hemolysis and release free heme, which in turn causes oxidative and inflammatory stress, leading to pain crises and ischemic damage. Hematologically, heme acts as a regulator of antioxidant and globin gene expression by binding to the transcriptional repressor BACH1, thereby reducing its suppressive effect on gene transcription. This interaction enhances the binding of nuclear factor erythroid 2-related factor 2 (NRF2) to antioxidant response elements (ARE), leading to increased transcription of genes such as heme oxygenase-1 (HMOX1), glutathione reductase (GR), solute carrier family 7 member 11 (SLC7A11), and NAD(P)H dehydrogenase [quinone] 1 (NQO1). Prior research has indicated that activating the NRF2 pathway in SCD mice can prevent heme-induced vascular obstruction, reduce inflammation, and lessen liver damage. Additionally, NRF2 activation boosts the production of A-gamma (HBG1) and G-gamma (HBG2) globins, which are components of hemoglobin F (HbF) that can replace βS-globins, thereby increasing HbF levels and reducing HbS in red blood cells.

Mitobridge is developing ML-0207/ASP8731, a potent and selective BACH1 inhibitor designed to activate the Nrf2 pathway in both human and mouse models. The company has studied ML-0207's capacity to regulate antioxidant and anti-inflammatory gene expression and to stimulate HbF in human cellular models and a preclinical mouse model of SCD. In human bone marrow-derived CD34+ cells that were differentiated into erythrocytes, ML-0207 induced the expression of Nrf2 target genes HGB1, HBG2, HMOX1, SLC7A11, GCLM, and NQO1. The use of 1 μM ML-0207 and 10 μM hydroxyurea (HU) resulted in a two-fold increase in CD71+/HbF+ erythrocytes compared to a control group. The combination of ML-0207 and HU was more effective in inducing HbF+ erythrocytes than either drug alone. In a single healthy donor who did not respond to 10 μM HU, ML-0207 at concentrations of 1 and 3 μM significantly induced CD71+/HbF+ cells. In Townes SCD mice, there was a significant increase in heme oxygenase 1 and a decrease in VCAM-1, ICAM-1, and phospho-p65 NF-κB protein levels. Additionally, there was a significant reduction in hemin-induced vaso-occlusion and an increase in the percentage of F-cells, which was associated with an increase in blood A-gamma globin and erythrocytes and a decrease in leukocytes. These findings suggest that BACH1 inhibitors could be a promising new treatment for SCD patients.