Oral Administration of the LSD1 Inhibitor ORY-3001 Increases Fetal Hemoglobin in Sickle Cell Mice and Baboons.

Increased levels of fetal hemoglobin (HbF) lessen the severity of symptoms and increase the life span of patients with sickle cell disease (SCD). More effective strategies to increase HbF are needed because the current standard of care, hydroxyurea, is not effective in a significant proportion of patients. Treatment of the millions of patients projected worldwide would best be accomplished with an orally administered drug therapy that increased HbF. LSD1 is a component of co-repressor complexes that repress γ-globin gene expression and a therapeutic target for HbF reactivation. Our laboratory has shown that subcutaneous administration of RN-1, a pharmacological LSD1 inhibitor, increased γ-globin expression in SCD mice and baboons, widely acknowledged as the best animal model to test the activity of HbFinducing drugs. The objective of this investigation was to test the effect of oral administration of a new LSD1 inhibitor, ORY-3001. Oral administration of ORY-3001 to SCD mice (n=3 groups) increased γ-globin expression, F cells and F retics. In normal baboons (n=7 experiments)treated with ORY-3001 increased F retics, γ-globin chain synthesis, and γ-globin mRNA were observed. Experiments in anemic baboons (n=2) showed that ORY-3001 increased F retics (PA8695, predose=24%, post=66.8%; PA8698: pre-dose=13%, post=93.6%), γ-globin chain synthesis (PA8695: pre-dose=0.07 γ/γ+β, post=0.20 γ/γ+β; PA8698: predose=0.02 γ/γ+β, post=0.44 γ/γ+β) and γ-globin mRNA (PA8695: predose=0.06 γ/γ+β, post=0.18 γ/γ+β; PA8698: pre-dose=0.03 γ/γ+β, post=0.33 γ/γ+β). We conclude that oral administration of ORY-3001 increased F retics, γ-globin chain synthesis, and γ-globin mRNA in SCD mice and in baboons, supporting further efforts toward the development of this drug for SCD therapy.