The BACH1 inhibitor ASP8731 inhibits inflammation and vaso-occlusion and induces fetal hemoglobin in sickle cell disease

• DOI: 10.3389/fmed.2023.1101501
• Publication Date: 2023-04-18T12:58:20Z
• Authors: John D. Belcher; Selvaraj Nataraja; Fuad Abdulla; Ping Zhang; Chunsheng Chen; Julia Nguyen; Conglin Ruan; Maneet Singh; Shilpa Demes; Lyndsay Olson; Domi Stickens; Jeff Stanwix; Emer Clarke; Yongzhao Huang; Margaret Biddle; Gregory M. Vercel...
• Keywords: HMOX1; Hemin

In sickle cell disease (SCD), heme released during intravascular hemolysis promotes oxidative stress, inflammation, and vaso-occlusion. Conversely, free can also activate expression of antioxidant globin genes. Heme binds to the transcription factor BACH1, which represses NRF2-mediated gene transcription. ASP8731, is a selective small molecule inhibitor BACH1. We investigated ability ASP8731 modulate pathways involved in SCD pathophysiology. HepG2 liver cells, increased HMOX1 FTH1 mRNA. pulmonary endothelial decreased VCAM1 mRNA response TNF-α blocked decrease glutathione hemin. Townes-SS mice were gavaged once per day for 4 weeks with hydroxyurea (HU) or vehicle. Both HU inhibited heme-mediated microvascular stasis combination, significantly reduced compared alone. mice, markedly oxygenase-1 hepatic ICAM-1, NF-kB phospho-p65 protein liver, white blood counts. addition, gamma-globin HbF+ cells (F-cells) as vehicle-treated mice. human erythroid differentiated CD34+ HGB percentage F-cells 2-fold manner similar HU. when given together induced more either drug from one donor that was non-responsive HU, ~2-fold. HBG HBA , but not HBB derived patients. These data indicate BACH1 may offer new therapeutic target treat SCD.