After a double-stranded DNA (dsDNA) breakage is deliberately made to the BCL11A gene by CRISPR/Cas9, the cell that harbors the DNA immediately initiates its DNA repair machinery to fix the damage. The cell’s preferred repair pathway approach is via non-homologous end joining (NHEJ) for dsDNA breaks that leave blunt ends. However, this repair system is prone to error in that mistakes are often made when joining the broken ends, as manifested by either an insertion or a deletion of nucleotides. It turns out that neither repair by insertion nor deletion works well in DNA repair and that deviations result in a blundered DNA sequence. Aberrancy is not tolerated to maintain DNA integrity; the faulty gene is silenced. This is precisely how BCL11A gets silenced by the newly approved drug Casgevy.
By clearing BCL11A, the suppressor over fetal hemoglobin gets removed and allows Hb F to be restored. It turns out that at six months of age, Hb F is suppressed mainly by BCL11A, but a low level of Hb F, ~0.6–0.8%, continues to exist. Of course, when BCL11A is silenced via CRISPR/Cas9, Hb F becomes fully restored, and adequate oxygen supply to the body’s tissues is also restored for sickle cell anemia patients.
