Potential role of LSD1 inhibitors in the treatment of sickle cell disease: a review of preclinical animal model data.

Sickle cell disease (SCD) is caused by a mutation of the β-globin gene (Ingram VM. Nature 180: 326-328, 1957), which triggers the polymerization of deoxygenated sickle hemoglobin (HbS). Approximately 100,000 SCD patients in the United States and millions worldwide (Piel FB, et al. PLoS Med 10: e1001484, 2013) suffer from chronic hemolytic anemia, painful crises, multisystem organ damage, and reduced life expectancy (Rees DC, et al. Lancet 376: 2018-2031, 2010; Serjeant GR. Cold Spring Harb Perspect Med 3: a011783, 2013). Hematopoietic stem cell transplantation can be curative, but the majority of patients do not have a suitable donor (Talano JA, Cairo MS. Eur J Haematol 94: 391-399, 2015). Advanced gene-editing technologies also offer the possibility of a cure (Goodman MA, Malik P. Ther Adv Hematol 7: 302-315, 2016; Lettre G, Bauer DE. Lancet 387: 2554-2564, 2016), but the likelihood that these strategies can be mobilized to treat the large numbers of patients residing in developing countries is remote. A pharmacological treatment to increase fetal hemoglobin (HbF) as a therapy for SCD has been a long-sought goal, because increased levels of HbF (α2γ2) inhibit the polymerization of HbS (Poillin WN, et al. Proc Natl Acad Sci USA 90: 5039-5043, 1993; Sunshine HR, et al. J Mol Biol 133: 435-467, 1979) and are associated with reduced symptoms and increased lifespan of SCD patients (Platt OS, et al. N Engl J Med 330: 1639-1644, 1994; Platt OS, et al. N Engl J Med 325: 11-16, 1991). Only two drugs, hydroxyurea and l-glutamine, are approved by the US Food and Drug Administration for treatment of SCD. Hydroxyurea is ineffective at HbF induction in ~50% of patients (Charache S, et al. N Engl J Med 332: 1317-1322, 1995). While polymerization of HbS has been traditionally considered the driving force in the hemolysis of SCD, the excessive reactive oxygen species generated from red blood cells, with further amplification by intravascular hemolysis, also are a major contributor to SCD pathology. This review highlights a new class of drugs, lysine-specific demethylase (LSD1) inhibitors, that induce HbF and reduce reactive oxygen species.