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Before you are born you make a different kind of haemoglobin, better suited to taking oxygen from your mother's blood. Shortly after birth a gene called BCL11A switches it off and adult haemoglobin takes over. In sickle cell disease and beta thalassemia the adult version is the problem — so if you disable the switch, the fetal version comes back and works fine. That is exactly what Casgevy does.
BCL11A encodes a zinc finger transcription factor that represses gamma-globin, effecting the fetal-to-adult haemoglobin switch. Casgevy disrupts the erythroid-specific +58 enhancer rather than the coding sequence, because BCL11A has essential functions elsewhere, particularly in B-lymphocyte development and the brain. Targeting a tissue-specific enhancer is what makes this intervention tolerable — an important general lesson about where to aim.
Sources
- Nature (Canver et al.) · 2015
BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis ↗