Off-target genomic DNA sites (mPPL-001)

Off-target genomic DNA sites refer to unintended locations in the human genome where a gene-editing tool, such as the mPPL-001 guide RNA, may bind and induce modifications. These sites typically possess partial sequence complementarity to the guide RNA and are adjacent to a compatible Protospacer Adjacent Motif (PAM), which is required for the CRISPR-associated (Cas) protein to initiate binding. In the context of mPPL-001, which is an experimental base-editing therapy designed to target the CCR5 gene for HIV resistance, off-target activity represents a significant safety concern. Unintended edits at these sites could lead to genotoxicity, including the disruption of tumor suppressor genes or the activation of oncogenes. Rigorous bioinformatic prediction and experimental validation, such as CHANGE-seq or GUIDE-seq, are employed to identify and minimize these risks during drug development. While mPPL-001 aims for high precision at the CCR5 locus, the potential for off-target effects remains a primary therapeutic challenge for all CRISPR-based modalities.

Other names

mPPL-001 off-targetsUnintended genomic cleavage sitesPartial complementarity sites