Novel HDAC Inhibitors for Treatment of Hemoglobinopathies

Project Summary Induction of normal but developmentally silenced fetal globin expression reduces anemia and ameliorates clinical severity in the beta hemoglobinopathies HDACs and are components of the NURD repressor complex which promotes silencing of fetal globin in adult cells Prior generation HDAC inhibitors have increased fetal globin in patients but had limitations for pharmaceutical application and required intermittent administration due to anti proliferative effects Cetya has generated a library of high potency HDAC inhibitors which can be readily modulated in chemical structure and has demonstrated their efficacy in inducing fetal globin induction in normal human erythroid cells including a select few candidates which do not shown undesirable growth inhibitory effects at fetal globin inducing concentrations The laboratory of Dr Perrine at Boston University will evaluate these candidates in progenitor cells cultured from sickle cell patients Dr Perrine has extensive experience in developing treatments for sickle cell and beta thalassemia This collaboration will explore this new high potency generation in HDAC chemistry to advance a therapeutic class to the clinic The studies proposed will identify an optimal HDAC inhibitor for subsequent development to an IND Aim To evaluate HDAC inhibitors for magnitude of fetal globin induction and anti proliferative effects in sickle cell erythroid progenitors and identify an optimal candidate for preclinical development Aim To increase the production scale of the selected candidate to support testing in IND required toxicology studies This proposal will evaluate novel histone deacetylase HDAC inhibitors for a new medical use in hemoglobinopathies serious blood diseases which confer life long morbidity and early mortality an annual US healthcare burden of andgt $ Billion and high childhood mortality internationally Preliminary evaluation of these HDAC inhibitors has demonstrated promising activity in the upregulation of fetal hemoglobin at concentrations where the relative absence of cellular toxicity is evident Upon completion of the proposed studies the most potent agent will be tested in animal models and if successful rapidly advanced into human clinical trials