To fix or not to fix - therapeutic RAG2 engineering

Mutations in the genes RAG1/2 (recombination-activation gene 1 and 2) in severe combined immunodeficiency (SCID) patients disrupt the maturation of T and B cells, which weakens the immune response to pathogens and may be lethal. Enabling proper expression of RAG1/2 that permits functional lymphocytes maturation is the only known cure. Since human donation carry a high risk of graft-versus-host disease, efforts are made to develop gene therapy treatment that will edit the patient's own cells using CRISPR-Cas9. This approach relays on a double-stranded cut of a specific gene and its replacement with an exogenous, correct sequence. This is by no means an easy task. The complexity of the human chromatin makes its repair extremely difficult, as every unplanned occurrence may potentially lead to catastrophic results. In a new article in Nature Communications, Dr. Ayal Hendel and his group present a novel RAG2 correction strategy, that replaces the entire coding sequence of the gene with maximum safety. Through this, the researchers demonstrate a proof-of-concept for the development of a safe and efficient gene therapy treatment.