Mutation-Specific CRISPR Targeting with SaCas9 and AsCas12a Restores Therapeutic Sensitivity in Treatment-Resistant Melanoma.

Melanoma remains one of the most challenging cancers to treat effectively with drug resistant remaining a constant concern, primarily with activating mutations. Mutations in the gene appear in approximately 50% of patients, 90% of which are V600E. Two frontline inhibitors (BRAFi), vemurafenib and dabrafenib, are frequently used to treat unresectable or metastatic V600E melanoma.

Homology directed correction, a new pathway model for point mutation repair catalyzed by CRISPR-Cas.

Gene correction is often referred to as the gold standard for precise gene editing and while CRISPR-Cas systems continue to expand the toolbox for clinically relevant genetic repair, mechanistic hurdles still hinder widespread implementation. One of the most prominent challenges to precise CRISPR-directed point mutation repair centers on the prevalence of on-site mutagenesis, wherein insertions and deletions appear at the targeted site following correction. Here, we introduce a pathway model for Homology Directed Correction, specifically point mutation repair, which enables a foundational analysis of genetic tools and factors influencing precise gene editing.