ORPHAGEN PHARMACEUTICALS, INC. — Department of Health and Human Services SBIR Phase I: NHLBI

Description

DESCRIPTION provided by applicant Inherited beta globinopathies including sickle cell disease SCD and thalassemia HLS are chronic blood disorders resulting from defects in hemoglobin Hb structure or synthesis These diseases affect an estimated people in the U S alone and much larger numbers in Africa Europe India the Middle East and the Caribbean The complications of SCD by far the most common beta globin disorder include hemolytic anemia painful ischemic crises bacterial infections stroke and chronic lung and kidney disease The major therapies for SCD and thalassemia include lifelong blood transfusions treatment with hydroxyurea a cytotoxic agent that modestly induces fetal hemoglobin HbF or high risk transplantation of hematopoietic cells Elevation of HbF is considered the most promising approach to treat SCD or to effect a remission or cure A benign condition hereditary persistence of fetal hemoglobinemia HPFH dramatically ameliorates or even prevents the symptoms of thalassemia and SCD Significantly in one form of HPFH naturally occurring mutations in the gene promoters of the fetal globin chains A and G induce HbF to of the level of globin in every red blood cell sufficient to inhibit SCD It has long been suggested that a pharmacological agent that replicates pancellular HbF induction could transform current therapy The goal of this Phase I SBIR proposal is to identify small molecule ligands to a transcription factor an orphan nuclear receptor NR that has a central role in silencing embryonic and fetal globin expression in the adult by binding to the promoters of the fetal globin genes To date no valid ligands have been described for this target Assay development and structural analysis also show that the NR target is likely to function similarly to other NRs such as the steroid retinoid and thyroid receptors by allosteri modulation of peptide affinity in response to ligand We developed a cell free high throughput screening HTS assay for this receptor that measures interaction with a short peptide derived from a transcriptional cofactor a putative corepressor for this orphan NR Our objective is to identify small molecules that disrupt corepressor peptide interaction with the orphan NR and to evaluate whether these negative modulators can derepress fetal globin expression In Aim we will screen diverse compound libraries in the biochemical HTS assay to identify small molecule ligands that disrupt the interaction between the orphan NR and corepressor peptide We will then determine in Aim whether in addition to regulating binding of corepressors the ligands identified in Aim also regulate corepressor interactions via the target receptor in cell culture We also propose to increase ligand affinity IC andlt M by purchase and synthesis of analogs to initial hits Finally in Aim we will test the ability of the identified ligands to ativate globin expression in hematopoietic cells cultured in vitro This pharmacological evaluation will enable more intensive drug discovery with SBIR Phase II support leading to testing of lead compounds in animal models of the globin disorders PUBLIC HEALTH RELEVANCE About Americans suffer from sickle cell disease and thalassemia Annual medical costs exceed $ billion Elevation of fetal hemoglobin HbF is considered a highly promising approach to treat SCD or the thalassemias since the effects of the defective or absent globin chain can be overcome by induction of fetal chain production Safe and effective therapies that elevate HbF will be rapidly accepted The goal of this Phase I project is to identify small molecule drug like compounds to a unique transcription factor that regulates the levels of HbF Our long term goal is development of a small molecule oral medication to treat these very serious inherited globin disorders