Abstract
Sickle-cell disease (SCD) is a debilitating hematological disorder with very few approved treatment options. Therapeutic reactivation of fetal hemoglobin (HbF) is one of the most pursued methods for ameliorating the systemic manifestations of SCD. Despite this, very few pharmacological agents have advanced to clinical trials or marketing for use. In this study, we report the development of an HbF in situ intracellular immunoblot assay coupled to a high-throughput drug screen to identify Food and Drug Administration (FDA) approved drugs that can be repurposed clinically for treatment of SCD. Using this assay we evaluated the National Institute of Health (NIH) Clinical Collection (NCC), a publicly available library of 725 small molecules, and found nine candidates that can significantly re-express HbF in erythroid cell lines as well as primary erythroblasts derived from SCD patients. Furthermore, we show the strong effects on HbF expression of these candidates to occur with minimal cytotoxicity in 7 of the 9 drugs. Given these data and their proven history of use for other indications, we hypothesize that several of these candidate drugs warrant further investigation for use in SCD.
Highlights
Sickle-cell disease (SCD) is a debilitating genetic disorder that affects millions of people worldwide
Given the long-term success of hydroxyurea in treating SCD, we focused efforts on developing an in situ HbF intracellular immunoblot assay coupled to a high-throughput drug screen to identify drugs that can be repurposed for treatment of SCD
Blood was obtained from healthy volunteers and sickle cell donors following written informed consent under a protocol approved by the Institutional Review Board (IRB) of The Ohio State University (OSU; Columbus, OH, USA) (IRB Protocol Number: 1997C0194) in accordance with the Declaration of Helsinki
Summary
Sickle-cell disease (SCD) is a debilitating genetic disorder that affects millions of people worldwide. Once sickled, affected RBCs are prone to binding to each other and the endothelium, which in turn blocks blood flow and causes severe pain as a direct consequence of ischemic injury to the surrounding tissue and organs This event is known as a vaso-occlusive crisis (VOC) and results in a systemic response in which the patient remains in a state of persistent, diffuse vascular inflammation [2,3]. Given the long-term success of hydroxyurea in treating SCD, we focused efforts on developing an in situ HbF intracellular immunoblot assay coupled to a high-throughput drug screen to identify drugs that can be repurposed for treatment of SCD This is a powerful, yet previously under-utilized methodology to screen for modulation of HbF from a library of drugs that have already been FDA approved for other indications. We present nine new drugs for repurposing in SCD that warrant future clinical investigation
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