X-linked hyper-IgM Syndrome (HIGM1) is a recessive genetic disorder that causes B cells to overproduce IgM antibodies and underproduce IgG, IgA, and IgE. In a healthy immune response, T cells signal B cells to undergo a process called “class switching recombination” in which the cell produces different classes of antibodies that will bind to a given antigen. HIGM1 is caused by inactivating mutations to the CD40LG gene resulting in disruption of the CD40 cell signaling pathway. Patients suffering from HIGM1 are susceptible to a variety of bacterial infections and have poor prospects for long term survival.
Correction of relevant mutations in T cells has long been explored as a strategy to cure HIGM1. In this paper, researchers at Vita-Salute San Raffaele University and San Raffaele Telethon Institute for Gene Therapy (SR-TIGET) compared two different gene correction strategies – autologous T cell therapy and hematopoietic stem/progenitor cell (HSPC) therapy. When they detected off-target editing at least one locus, the research team switched to Aldevron SpyFi™ Cas9 Nuclease to reduce this off-target activity below detectable levels. Both T-cell and HPSC therapeutic approaches were effective at rescuing immune response in mouse models, but the research team ultimately concluded that T-cell therapy would be a more promising clinical strategy.
Vavassori, V., Mercuri, E., Marcovecchio, G. E., Castiello, M. C., Schiroli, G., Albano, L., Margulies, C., Buquicchio, F., Fontana, E., Beretta, S., Merelli, I., Cappelleri, A., Rancoita, P. M., Lougaris, V., Plebani, A., Kanariou, M., Lankester, A., Ferrua, F., Scanziani, E., Cotta-Ramusino, C., … Genovese, P. (2021). Modeling, optimization, and comparable efficacy of T cell and hematopoietic stem cell gene editing for treating hyper-IgM syndrome. EMBO molecular medicine, 13(3), e13545. https://doi.org/10.15252/emmm.202013545