The long term goal of this project is a selective Histone Deacetylase 1 and 2 (HDAC1/2) inhibitor for the treatment of patients with the beta-hemoglobinopathies sickle cell anemia and beta- thalassemia. An estimated 400,000 children are born each year with one of these hemoglobin disorders. Few treatments exist to alleviate the symptoms of hemoglobinopathies and none are approved for children. Sickle cell anemia and beta-thalassemia remain an unmet medical need and a large public health burden. Reactivation of the expression of fetal hemoglobin can reverse many of the symptoms of beta hemoglobinopathies. Thus far treatments that induce expression of fetal hemoglobin also decrease or disrupt normal cell division and are associated with severe side effects. Recently the role of HDAC1 and 2 in the suppression of fetal hemoglobin expression was shown by genetic ablation of these genes. Compounds that are selective for HDAC1 and 2 versus other HDACs can induce the expression of fetal globin in adult erythroid cells. We have generated a set of selective HDAC1/2 inhibitors with drug like properties. We plan to advance one of these compounds into pre-clinical development for beta hemoglobinopathies. We will test the activity of these compounds at inducing fetal globin gene expression in adult erythroid cells. We will also determine if this induction of fetal globin is accompanied by changes in erythroid cell division or differentiation. We will confirm that our compounds can induce fetal hemoglobin in cells from patients with beta-hemoglobinopathies. Finally, we will explore the mechanism of action of HDAC1/2 inhibition by examining changes in chromatin structure and function in the beta globin locus. The final product of this Phase I project will be a selective HDAC1/2 inhibitor that can induce fetal hemoglobin in adult erythroid cells that will be advanced as a candidate for pre-clinical development. A Phase II project building off of this work would further advance the molecule through development toward filing of an IND for beta hemoglobinopathies.
Public Health Relevance Statement: Public Health Relevance: An estimated 400,000 children are born each year with one of these hemoglobin disorders. Few treatments exist to alleviate the symptoms of hemoglobinopathies and none are approved for children. Sickle cell anemia and beta-thalassemia remain an unmet medical need and a large public health burden. This project aims to generate an inhibitor of histone deacetylase 1 and 2 as a new therapeutic for these hemoglobinopathies.
NIH Spending Category: Cooley's Anemia; Genetics; Hematology; Orphan Drug; Pediatric; Rare Diseases; Sickle Cell Disease; Stem Cell Research; Stem Cell Research - Nonembryonic - Human
Project Terms: Ablation; Adult; Adverse effects; Affect; base; beta Globin; beta Thalassemia; Bioavailable; Biological Assay; Birth; Blood Cells; Bone Marrow Stem Cell; CD34 gene; Cell Differentiation process; Cell division; Cells; Child; Chip seq; chromatin immunoprecipitation; Chromatin Structure; Clinical; Conceptions; cytotoxic; Development; Disease; Drug Kinetics; Embryo; Enzymes; epigenetic marker; Erythroid Cells; Erythroid Progenitor Cells; fetal; fetal globin; Fetal Hemoglobin; Gene Expression; Genes; Genetic; Globin; Goals; HDAC1 gene; HDAC3 gene; Hematopoiesis; Hemoglobin; Hemoglobinopathies; Hereditary Disease; Histone Deacetylase; Human; human HDAC1 protein; hydroxyurea; improved; In Vitro; Individual; inhibitor/antagonist; Life; Medical; meetings; Mutation; Newborn Infant; Normal Cell; novel therapeutics; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Population; pre-clinical; prevent; Production; Property; public health medicine (field); public health relevance; Rattus; Reporting; response; RNA Interference; Role; Safety; Series; Severities; Sickle Cell; Sickle Cell Anemia; small molecule; Staging; Stem cells; Symptoms; Testing; Thalassemia; Therapeutic Agents; Transcript; Transfusion; Work
