An emerging strategy for the treatment of sickle cell anemia and the beta-thalassemias is reactivation of gamma globin, the fetal hemoglobin gene (HbF). HbF expression supports early mammalian development giving way to alpha and beta globin expression during adulthood. This temporal regulation of globin gene expression is reflected at the level of chromatin structure of the globin locus. The HbF gene is silenced by changes in chromatin structure that block access of transcriptional activators to promoter and enhancer regions. This silencing is mediated in part by localized histone deacetylation catalyzed by histone deacetylases (HDAC). These chromatin changes are reversible; the HbF protein can be reactivated in anemic adults expressing mutated odl3-globins. Chemical inhibitors of HDAC lead to more acetylated histones thereby reactivating silenced genes. Although, a number of HDAC inhibitors are known, their toxicological and pharmacokinetic profiles are inconsistent with long-term therapy. Animal studies and clinical trials using the current HDAC inhibitors often resort to administration by infusion or suboptimal levels of oral dosing, thus limiting efficacy and/or increasing toxicity. In Phase I of this SBIR Fast-Track proposal, Kalypsys, Inc. will carry out comprehensive studies to identify and characterize novel inhibitors of HDAC. An ultra-high throughput screen of nearly 500,000 compounds will identify hits for further medicinal chemistry optimization. In Phase II, secondary assays will test the ability of these compounds to reactivate HbF in cell culture models. Potent leads will be further refined for optimal pharmacokinetic and non-toxic properties in animals. Optimized compounds will be tested in animal models of sickle cell disease to establish in vivo efficacy using criteria that include increases in HbF expression and reticulocyte number. PROPOSED COMMERCIAL APPLICATION: There is significant unmet need for a safe and effective long-term therapy for patients with sickle cell disease (SCD). It is estimated that over 300,000 people are born each year with this disease, generating between $0.5-$2 billion annually in health care costs in the United States alone. It is anticipated that this work will generate a desperately needed long-term therapy for SCD.
Thesaurus Terms: blood /lymphatic pharmacology, blood disorder chemotherapy, enzyme inhibitor, globin, hemoglobin F, sickle cell anemia, therapy design /development amidohydrolase, combinatorial chemistry, cytotoxicity, drug interaction, gene expression, nonhuman therapy evaluation, pharmacokinetics, reticulocyte flow cytometry, genetically modified animal, high throughput technology, laboratory mouse, polymerase chain reaction, tissue /cell culture
