Abstract
Genetic defects in recombination activating genes (RAG) 1 and 2 cause a broad spectrum of severe immune defects ranging from early severe and repeated infections to inflammation and autoimmune manifestations. A correlation between in vitro recombination activity and immune phenotype has been described. Hematopoietic cell transplantation is the treatment of care; however, the availability of next generation sequencing and whole genome sequencing has allowed the identification of novel genetic RAG variants in immunodeficient patients at various ages, raising therapeutic questions. This review addresses the recent advances of novel therapeutic approaches for RAG deficiency. As conventional myeloablative conditioning regimens are associated with acute toxicities and transplanted-related mortality, innovative minimal conditioning regimens based on the use of monoclonal antibodies are now emerging and show promising results. To overcome shortage of compatible donors, gene therapy has been developed in various RAG preclinical models. Overall, the transplantation of autologous gene corrected hematopoietic precursors and the use of non-genotoxic conditioning will open a new era, offering a cure to an increasing number of RAG patients regardless of donor availability and severity of clinical conditions.
Highlights
Effective adaptive immunity relies on the ability of T and B lymphocytes to express the vast majority of antigen receptors
T and B cells assemble T cell antigen receptor (TCR) and B cell receptor (BCR) respectively, by a complex process named V(D)J recombination that recognizes each segment of V, D and J flanked by recombination signal sequences (RSSs) [1]
The T- B- natural killer (NK)+ severe combined immunodeficiency (SCID) phenotype is characterized by repeated severe infections caused by common viral pathogens and opportunistic pathogens that lead to death in the absence of hematopoietic stem cell transplantation (HSCT), which represents the treatment of choice [3]
Summary
Effective adaptive immunity relies on the ability of T and B lymphocytes to express the vast majority of antigen receptors. New Therapies for RAG molecular studies have defined the biochemical effect of amino acid changes on the recombination activity, providing evidence that residual activity sustained at least by one allele can lead to a peculiar immune phenotype named Omenn syndrome (OS) [4, 5] These patients present severe erythroderma, lymphadenopathy with hepatosplenomegaly, colitis, repeated infections and inflammatory pneumonitis. ACK2 synergistically acted with low-dose irradiation or CD47 blockade to allow higher engraftment in XCGD [51] or immunocompetent mice [52], respectively These data paved the way for the clinical trial using anti-CD117 antibody currently ongoing to treat SCID patients (NCT02963064) [33], which provides the proof of concept that a humanized mAb can safely clear human hematopoietic stem cells (HSC) niches facilitating donor cell engraftment in two T-B-NK+ SCID patients (with Artemis mutations) [53].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
