The paper concludes that gene editing reduces random HBV integration by 60% (in PHHs) and up to 80% (in the Tg-HBV mouse model). However, in the HBV-infected PHHs (Figure 2D & 2E), the authors observe a “modest spike” in integration events near the two intended target sites. This suggests that while global integration is reduced, the nuclease may be actively promoting the integration of cleaved viral fragments at these specific loci. Did the authors quantify the absolute number of these on-target integration events to ensure the reduction in global integration is not offset by a localized increase in potentially oncogenic insertions near the target sites? Could the chimeric reads near the cut sites not represent de novo integration of episomal DNA but rather the result of chromosomal deletions extending outward from a pre-existing integration event, which would be a different and potentially more dangerous outcome?
