この遺伝子の働き
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 ↗