Identification of Potential Therapeutics for the Treatment of β-Thalassemia
Abstract
1 in 100,000 people globally are suffering from severe β-thalassemia and an estimated 1.5 percent of the world's population (80 to 90 million people) is a carrier of a β-thalassemia-causing mutation (Cao and Galanello 2010 and De Sanctis et al. 2017). A common cause of β-thalassemia are mutations in the HBB gene that interfere with the normal splicing of the beta hemoglobin transcript (Thein 2013). The IVSI-6 T>C HBB, prevalent in the Mediterranean and Middle Eastern populations, and the more severe IVSI-5 G>C HBB mutation, prevalent in South Asian populations, weaken the normal (wild-type) intron 1 5’ splice donor site in HBB and activate three nearby cryptic sites (+12, -16, -38). The HbE-causing mutation, prevalent in the Southeast Asian population and found in half of all patients with clinically significant β-thalassemia, increases the utilization of the cryptic -16 splice site in exon 1 of HBB pre-mRNA (Galanello and Origa 2010). The findings presented in this study provide evidence that the splicing pattern generated by HBB bearing the IVSI-6 HBB, IVSI-5 HBB, and HbE causing mutation can be modulated by commonly consumed chemical compounds. Carnosol, a phenolic diterpene found in rosemary, reduces the production of the correctly spliced transcript generated by the HBB gene bearing mutations that activate the -16 cryptic splice site in exon 1. These data suggest patients bearing the IVSI-6 HBB, IVSI-5 HBB, or HbE causing mutations may benefit from avoiding carnosol-containing foods. Spironolactone (a commonly prescribed FDA-approved drug) and its metabolites facilitate production of the correctly spliced transcripts generated by HBB bearing mutations that activate the -16 cryptic splice site in exon 1. Subsequently, spironolactone enhances the production of the β-hemoglobin protein. Spironolactone and its metabolites may be therapeutic for patients carrying these mutations. The findings generated in this study support ongoing screening efforts aimed at identifying splice-altering compounds that may impact the health of individuals bearing splice-altering mutations in HBB.
Subject Area
Molecular biology|Cellular biology|Biology
Recommended Citation
Fasih-Ahmad, Faaria, "Identification of Potential Therapeutics for the Treatment of β-Thalassemia" (2023). ETD Collection for Fordham University. AAI30487059.
https://research.library.fordham.edu/dissertations/AAI30487059
