A new gene editing strategy has been developed as a potential treatment for certain patients with severe combined immunodeficiencies (SCID).
Dr Ayal Hendel of Bar-Ilan University in Israel, and colleagues, have looked into the use of genome-editing CRISPR-Cas9 technology which allows for precise gene editing by making breaks in DNA. In particular, the team tested ‘Homology-directed repair (HDR)-mediated’ gene editing, for its use in some severe subtypes of SCID with mutations to the RAG2 gene.
They believe it could be an effective alternative to allogeneic haematopoietic stem cell transplantation.
In Nature Communications, the authors write: “Severe combined immunodeficiency (SCID) is a group of multiple rare monogenic disorders characterised by defects in both cellular and humoral adaptive immunity.
“Patients are born healthy and due to being extremely susceptible to pathogens, they present with recurrent infections early in life which if left untreated can be fatal.”
The RAG2 gene is critical in the development of a healthy immune system, and mutations in the gene lead to SCID. However, the challenge when it comes to replacing the RAG2 gene is that its activity is tightly controlled such that it needs to be activated only in certain cells, in the right places in the body at the right time. Traditional gene therapy techniques do not take this into account, the authors argue.
However, they explain that “manipulation of a patient’s own haematopoietic stem and progenitor cells using CRISPR-Cas9 gene editing could provide a therapeutic alternative”.
“We show an innovative RAG2 correction strategy,” they add. “Our proof-of-concept study holds promise for safer gene therapy techniques of tightly regulated genes.”
Dr Hendel said that “by preserving endogenous regulatory elements and intronic sequences” in CRISPR-Cas9 HDR-mediated gene editing, “our approach faithfully reproduces natural gene expression levels, thus reducing the associated risks of unregulated gene expression”.
He believes: “This groundbreaking technique, which involves replacing entire coding sequences or exons while retaining critical regulatory elements, brings hope to patients with RAG2-SCID and holds promise for the treatment of various other genetic disorders.”
Allen D, Knop O, Itkowitz B, Kalter N, Rosenberg M, Iancu O, Beider K, Lee YN, Nagler A, Somech R, Hendel A. (2023) “CRISPR-Cas9 engineering of the RAG2 locus via complete coding sequence replacement for therapeutic applications.” Nature Communications, doi: 10.1038/s41467-023-42036‑5
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