| First Author | Peterson KR | Year | 2014 |
| Journal | PLoS One | Volume | 9 |
| Issue | 9 | Pages | e107006 |
| PubMed ID | 25225870 | Mgi Jnum | J:222513 |
| Mgi Id | MGI:5644770 | Doi | 10.1371/journal.pone.0107006 |
| Citation | Peterson KR, et al. (2014) A cell-based high-throughput screen for novel chemical inducers of fetal hemoglobin for treatment of hemoglobinopathies. PLoS One 9(9):e107006 |
| abstractText | Decades of research have established that the most effective treatment for sickle cell disease (SCD) is increased fetal hemoglobin (HbF). Identification of a drug specific for inducing gamma-globin expression in pediatric and adult patients, with minimal off-target effects, continues to be an elusive goal. One hurdle has been an assay amenable to a high-throughput screen (HTS) of chemicals that displays a robust gamma-globin off-on switch to identify potential lead compounds. Assay systems developed in our labs to understand the mechanisms underlying the gamma- to beta-globin gene expression switch during development has allowed us to generate a cell-based assay that was adapted for a HTS of 121,035 compounds. Using chemical inducer of dimerization (CID)-dependent bone marrow cells (BMCs) derived from human gamma-globin promoter-firefly luciferase beta-globin promoter-Renilla luciferase beta-globin yeast artificial chromosome (gamma-luc beta-luc beta-YAC) transgenic mice, we were able to identify 232 lead chemical compounds that induced gamma-globin 2-fold or higher, with minimal or no beta-globin induction, minimal cytotoxicity and that did not directly influence the luciferase enzyme. Secondary assays in CID-dependent wild-type beta-YAC BMCs and human primary erythroid progenitor cells confirmed the induction profiles of seven of the 232 hits that were cherry-picked for further analysis. |
