RN-1, a potent and selective lysine-specific demethylase 1 inhibitor, increases γ-globin expression, F reticulocytes, and F cells in a sickle cell disease mouse model

Abstract

Increased levels of fetal hemoglobin are associated with decreased symptoms and increased lifespan in patients with sickle cell disease (SCD). Hydroxyurea, the only drug currently approved for SCD, is not effective in a large fraction of patients, and therefore, new agents are urgently needed. Recently it was found that lysine demethylase 1, an enzyme that removes monomethyl and dimethyl residues from the lysine 4 residue of histone H3, is a repressor of γ-globin gene expression. In this article, we have compared the ability of tranylcypromine (TCP) and a more potent TCP derivative, RN-1, to increase γ-globin expression in cultured baboon erythroid progenitor cells and in the SCD mouse model. The results indicate that the ability of RN-1 to induce F cells and γ-globin mRNA in SCD mice is similar to that of decitabine, the most powerful fetal hemoglobin-inducing drug known, and greater than that of either TCP or hydroxyurea. We conclude that RN-1 and other lysine demethylase 1 inhibitors may be promising new γ-globin-inducing agents for the treatment of SCD that warrant further studies in other preclinical models, such as nonhuman primates.

The LSD1 inhibitor RN-1 recapitulates the fetal pattern of hemoglobin synthesis in baboons (P. anubis)

“…31 Two recent studies have shown that RN-1, a more potent and specific LSD-1 inhibitor than TCP, induced γ-globin expression in human and baboon erythroid progenitors and a sickle cell mouse model. 32,33 In this study we have tested the effect of RN-1 in baboons and confirm that it is a highly potent in vivo inducer of HbF synthesis.…”

“…The results confirm and extend our previous studies in the sickle cell mouse model showing that RN-1 increased F cells, F reticulocytes, and γ-globin mRNA to levels similar to decitabine, the most potent HbF-inducer known. 32,33 However, both these drugs elicit only small increases of γ-globin expression in the SCD mouse model compared to the magnitude observed in baboons, emphasizing the importance of using nonhuman primate, such as baboons, to test the effect of HbFinducing drugs.…”

Pharmacological inhibition of LSD1 and mTOR reduces mitochondrial retention and associated ROS levels in the red blood cells of sickle cell disease

“…Second, we show that RBCs with mitochondria are associated with high levels of ROS accumulation. Finally, we demonstrate that two preclinical candidate drugs, the LSD1 inhibitor, RN-1(12, 13) and mTOR inhibitor(14), Sirolimus, both reduce levels of mitochondria retaining RBCs in a SCD mouse model.…”

“…injection to homozygous SCD mice five days a week for 2 to 4 weeks as previously described (12). For mTOR inhibition, Sirolimus (Rapamycin-Selleck chemicals) was given at a dose of 5mg/kg by intraperitoneal (i.p.)…”

Animal models of β-hemoglobinopathies: utility and limitations

“…Although the baboon closely reiterates the structure and switching of the human β-globin locus, the inherent complexities of primate research have limited the number of such studies. Nevertheless, valuable insights have been gained, particularly in preclinical testing of novel therapeutic inducers 84–86…”