Preprint: Cas9–DNA repair protein fusions fail to improve homing gene drive efficiency in Drosophila

A bioRxiv preprint from researchers working with Drosophila melanogaster reports a systematic test of eight Cas9 constructs fused to DNA repair-associated proteins previously shown to improve homology-directed repair (HDR) in conventional genome editing contexts. The motivation for the study is a central challenge in CRISPR homing gene drive design: competing end-joining repair pathways generate resistance alleles — variants that can no longer be converted by the drive — limiting the spread of drive alleles through a target population.

The team tested whether fusing Cas9 to proteins that promote HDR could reduce resistance allele formation and improve drive performance, but found that none of the eight fusion constructs produced a consistent improvement relative to unfused Cas9 controls. The authors suggest the biology of gene drives — where Cas9 acts on the endogenous locus in the germline context — may be sufficiently different from standard editing in somatic cells or early embryos that repair-factor fusions do not confer the same advantage.

The negative result is scientifically informative for the gene drive field, which is exploring potential population suppression applications in insects that transmit diseases or threaten ecosystems. Understanding which engineering strategies do and do not scale to drive contexts is important for directing future development effort.

This is a preprint and has not undergone peer review.