CRISPR/Cas9 breaks the double-stranded DNA (dsDNA), and the cell’s instinctual and immediate reaction is to repair the damage to save the cell. For dsDNA break that leaves blunt ends, the cell’s preferred approach of repair pathway is via the non-homologous end joining (NHEJ). This repair system is prone to errors in the process of joining the broken ends, mistakes often occur manifested by either an insertion or a deletion of nucleotides, neither of which is desirable. These deviations result in an aberrant DNA sequence and subsequent silencing of the gene encoded by the DNA sequence.
This idea of CRISPR-mediated gene silencing was applied to a breakthrough gene therapy achieved by CRISPR/Cas9. The resultant cell therapy drug is Casgevy with the generic name exagamglogene autotemcel, which received FDA approval on December 8, 2023, for treating sickle cell disease and its associated anemia.15 Over the next few pages, a review of the mechanism of action of Casgevy is discussed, starting with background information on sickle cell anemia as it pertains to sickle cell disease.
