New Therapeutic Target for Sickle Cell Disease

WASHINGTON, August 31, 2020 (Newswire.com) - ​​​An article published in Experimental Biology and Medicine (Volume 245, Issue 15, September 2020) (https://journals.sagepub.com/doi/pdf/10.1177/1535370220945305) details a possible future treatment option for patients with sickle cell disease. The study, led by Drs. Xingguo Zhu and Betty S. Pace in the Division of Hematology/Oncology within the Department of Pediatrics at Augusta University in Augusta, GA, (USA), reports that NRF2, a transcription factor which controls oxidative stress in red blood cells, regulates globin gene expression. 

Sickle cell disease (SCD) is an inherited disorder caused by a mutation in the adult hemoglobin A gene that results in the production of abnormal hemoglobin S.  Hemoglobin is the major protein inside red blood cells and delivers oxygen to cells throughout the body. In SCD, red blood cells lose their round shape and can stick to small blood vessels and white blood cells which blocks blood flow resulting in pain, acute chest syndrome and stroke. Prior studies have demonstrated that inducing expression of fetal hemoglobin, which is silenced at birth, can lessen the severity of SCD. Hydroxyurea, which was the first FDA-approved therapeutic for SCD, works in part by increasing fetal globin. Nonetheless, some patients do not respond to treatment with hydroxyurea, and there is an urgent need to identify new molecular targets for increasing fetal globin expression in patients with SCD.  

In the current study, Dr. Zhu and colleagues developed a novel betaYAC/NRF2 knockout mouse model to study the role of NRF2, a transcription factor which controls oxidative stress in red blood cells, in fetal hemoglobin expression. Deletion of NRF2 suppressed fetal hemoglobin expression during mouse development and altered epigenetic DNA and histone modifications. These findings demonstrate a new function for NRF2 in fetal globin gene expression and support targeting NRF2 to increase fetal globin expression and alleviate clinical symptoms in SCD patients. Dr. Zhu said “Testing additional small chemical compounds that activate NRF2 will identify new drugs for treating SCD.” Dr. Pace added that “The betaYAC/NRF2 knockout mouse provides a novel tool for researchers in the field to use for learning more about globin gene regulation.”

Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology & Medicine, said “Dr. Zhu and colleagues have utilized a transgenic β-YAC/NRF2 mouse model to demonstrate the molecular mechanisms underlying the regulation of fetal globin expression by the NRF2 transcription factor. Their studies demonstrate that therapeutics that enhance NRF2 expression should enhance fetal globin expression reducing the severity of SCD. Further, they supply a mouse model for small molecule drug development testing.”

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Source: Experimental Biology and Medicine