Genereplacement

Genereplacement is a term used to describe replacing a gene in an organism's genome with a different DNA sequence. The term is not widely standardized, and many authors prefer gene replacement or knock-in. In essence, genereplacement involves introducing a donor sequence that is integrated at the target locus to modify gene function.

Techniques include classical homologous recombination in cells and model organisms, and modern genome editing approaches such as CRISPR-Cas9–mediated replacement, where a double-strand break at the target site is repaired using a donor template with homologous arms. Other methods employ adeno-associated viral vectors or other delivery systems to introduce the replacement cassette.

Applications span basic research, disease modeling, and therapeutic development. Gene replacement can create precise allele replacements to study gene function, model pathogenic mutations, or restore normal gene activity in cells. In clinical contexts, translating gene replacement requires careful consideration of delivery, efficiency, tissue targeting, and long-term safety.

Challenges include off-target effects, incomplete replacement, delivery barriers, and mosaicism. Ethical and regulatory issues arise, especially for germline or heritable replacement. Ongoing research seeks to improve efficiency and specificity and to establish standards for safety, efficacy, and equitable access. Related topics include gene therapy, genome editing, and knock-in strategies.