Gamma-globin promoter -175 adenine (HBG -175A)

The target is a specific adenine nucleotide located at the -175 position within the promoters of the HBG1 and HBG2 genes, which encode the gamma-globin subunits of fetal hemoglobin (HbF) (Source: Beam Therapeutics, 2024). This site is a known hotspot for mutations that lead to Hereditary Persistence of Fetal Hemoglobin (HPFH), a condition where individuals continue to produce high levels of HbF into adulthood (Source: PubMed, PMID: 3010352). In therapeutic applications, an adenine base editor (ABE) complexed with a specific single-guide RNA (sgRNA) is used to precisely convert this adenine to guanine, mimicking the HPFH -175 T>C mutation (Source: Nature Medicine, 2021). This genetic modification disrupts the binding of repressors like BCL11A or creates a binding site for activators, effectively switching on HbF production (Source: Blood, 2022). This approach is primarily investigated for treating hemoglobinopathies such as sickle cell disease and beta-thalassemia, where the induced HbF can compensate for the lack of functional adult hemoglobin (Source: NIH, ClinicalTrials.gov). By targeting the -175 position, researchers aim to provide a durable, one-time genetic treatment that restores healthy red blood cell function (Source: Beam Therapeutics).

Other names

HBG1/HBG2 promoter -175 positionHPFH -175 siteGamma-globin gene promoter -175AHBG1 promoter adenine at -175HBG2 promoter adenine at -175

Adenine base editing (ABE) to induce an A-to-G transition at the -175 position of the HBG1 and HBG2 promoters, which mimics a naturally occurring HPFH mutation and leads to the reactivation of fetal hemoglobin (Source: Beam Therapeutics).