Targeting LSD1 to Induce HbF
Pharmacologic augmentation of HbF is a therapeutic target in β hemoglobinopathies. HbF can inhibit sickle hemoglobin (HbS) polymerization and replace deficient adult hemoglobin in in β thalassemia and additional therapeutics are needed. We identified lysine-specific demethylase 1 (LSD1) as a new enzyme component within a large complex that regulates HbF gene expression. In vivo inhibition of LSD1 by the small chemical inhibitor RN-1 in a mouse model of sickle cell disease induced HbF synthesis and led to improvement in many aspects of the disease pathology suggesting that LSD1 comprises a useful molecular target for possible therapeutic intervention. We are comparing the activity of RN-1 and candidate analogs in erythroid cells cultured from human umbilical cord blood-derived erythroid progenitors and selecting the optimal drug for in vivo testing. We also are comparing the effects of RN-1 treatment and other analogs that exhibit more favorable drug characteristics, in humanized sickle cell mice and determining PK and metabolism of RN-1 and promising analogs to help determine dosing for baboon and human trials. Previously reported HDAC, DNMT and other inhibitors have never exhibited the same degree of specificity and non-cytotoxicity as does RN-1. RN-1 is a promising lead compound for developing novel HbF-inducing agents based on LSD1 inhibition for safer and more effective therapeutics for the β hemoglobinopathies.