Inactivation of LSD1 as a possible treatment for sickle cell disease

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DESCRIPTION (provided by applicant): Sickle cell disease (SCD) and b-thalassemia together comprise the most commonly inherited diseases in man. The only current therapy for SCD is treatment with hydroxyurea (HU). HU induces fetal hemoglobin (HbF) synthesis in about half of treated patients by as yet unknown mechanism(s), and its long term effects are largely unknown. HbF induction is known clinically to reduce organ morbidity and pain in SCD patients, and to inhibit sickle polymer formation and consequently destruction of erythrocytes in vitro. For the past decade, my lab has studied a fetal g-globin gene repressor called DRED. We recently reported the subunit composition of DRED, which is composed of at least four distinct epigenetic modifier co-repressor multiprotein complexes. One of the modifying enzymes is LSD1, a monoamine oxidase that removes activating chromatin signatures, thereby leading to gene repression. We recently tested a highly specific inhibitor for LSD1 called tranylcypromine (TC). We found that in human CD34+ hematopoietic stem cells induced to differentiate into erythroid cells in vitro, HbF was induced to therapeutic levels in a TC dosage-dependent manner. We have filed a novel use patent for TC, which is already FDA approved and off patent, and intend to test for cryptic properties (HbF induction) in cells and sickle cell mice. Should these preliminary tests be fruitful, we will in the future then initiate clinical trials in ealthy and sickle cell patients. PUBLIC HEALTH RELEVANCE: Hemoglobinopathies are the most common inherited disorders in man. Correlative clinical evidence suggests that g-globin replacing bS globin in sickle red cells is therapeutic for SCD. A feasibly attractive strategy to induce g-globin synthesi would be to inactivate a regulatory protein that normally functions to repress g-globin synthesis in adult erythroid precursor cells. We recently identified the enzyme LSD1 as one of the components of a core g-globin repressor complex. Most recently, we discovered that in human CD34+ hematopoietic stem cells induced to differentiate into erythroid cells, reduction of intracellular LSD1 activity via LSD1 mRNA degradation or inhibition of LSD1 catalytic action led to dramatic induction of fetal hemoglobin levels ex vivo. This proposal explores the initial hypothesis that Parnate, an FDA-approved antidepressant, could be used to treat SCD.