Gene regulation of developmental hemoglobin switching holds the potential for therapeutic relief from all symptoms associated with Sickle Cell Disease (SCD). Reactivation of fetal gamma-globin expression (HbF) can replace mutant betaS-globin (HbS) to produce functional hemoglobin tetramers and eliminate the hemoglobin polymerization that is characteristic of sickled red blood cells. We have discovered a protein that regulates this developmental switch, and have identified a compound that stimulates expression of this protein. EdX-17 promotes expression of the anti-stress factor ferritin heavy chain (FtH), which enters the nucleus of erythroid precursor cells and activates expression of fetal gamma-globin, producing HbF (PNAS 98:9145-50, 2001; Blood 108:790a, 2006). Mononuclear cells were isolated from SCD patient blood and matured in vitro to the advanced erythroblast stage using a 28-day, 2-phase culture system (Methods in Molecular Biology 482:127-40, 2009; Blood 119:6296-306, 2012). Treatment with EdX-17 for 24h resulted in a dose-responsive induction of gamma-globin gene expression and a concomitant dose-responsive increase in HbF was observed after 28 days in culture. These studies demonstrate that EdX-17 doses in the picomolar range are sufficient to significantly enhance HbF. Furthermore, EdX-17 treatment reconstitutes fetal hemoglobin (HbF) in transgenic betaYAC mice to levels above 25-30% - the range thought to be sufficient to ameliorate symptoms of SCD – with no detectable ill effects. In fact, mice treated with EdX-17 tend to have shinier coats, are more alert and stronger than age-matched, untreated mice. Development of this novel therapeutic is expected to ameliorate SCD symptoms, decrease pain and morbidity, increase life-span, greatly improve patient quality of life, and significantly reduce treatment costs. Supported in part by The Sickle Cell Cure Foundation, Inc., the Bill & Melinda Gates Foundation, and EpimedX, LLC.
Disclosures
Broyles: EpimedX, LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Curtis:EpimedX, LLC: Employment, Equity Ownership, Research Funding. Roth:EpimedX, LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Floyd:EpimedX, LLC: Employment, Equity Ownership, Research Funding. Belegu:EpimedX, LLC: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Floyd:EpimedX, LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding.
