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Some jobs need more than one change. An off-the-shelf cell therapy needs the donor cell's own receptor removed so it does not attack the patient, and its identity markers removed so the patient does not destroy it, and often a brake taken off so it keeps working. That is three or more edits in one cell — and every extra cut is an extra chance for two breaks to be joined to each other by mistake.
Multiplex editing introduces several simultaneous modifications, essential for allogeneic cell products requiring TRAC, B2M and often CIITA or PDCD1 disruption. The dominant risk is translocation between concurrent double-strand breaks, which scales with the number of cuts. Sequential editing, base editors (which do not create double-strand breaks) and Cas12a's self-processing guide arrays are all used to mitigate it.
Why base editing helps here
Base editors can disrupt a gene by installing a stop codon or destroying a splice site, without ever cutting both strands. With no free DNA ends there is nothing to join wrongly, so translocation risk essentially disappears. That is a substantial argument for base editing in multiplexed cell therapy, independent of any argument about precision.
Sources
- National Human Genome Research Institute
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