Journal article Open Access

Modeling, optimization, and comparable efficacy of T cell and hematopoietic stem cell gene editing for treating hyper-IgM syndrome

Vavassori, Valentina; Mercuri, Elisabetta; Marcovecchio, Genni E.; Castiello, Maria C.; Schiroli, Giulia; Albano, Luisa; Margulies, Carrie; Buquicchio, Frank; Fontana, Elena; Beretta, Stefano; Merelli, Ivan; Cappelleri, Andrea; Rancoita, Paola M.V.; Lougaris, Vassilios; Plebani, Alessandro; Kanariou, Maria; Lankester, Arjan; Ferrua, Francesca; Scanziani, Eugenio; Cotta-Ramusino, Cecilia; Villa, Anna; Naldini, Luigi; Genovese, Pietro


Precise correction of the CD40LG gene in T cells and hematopoietic stem/progenitor cells (HSPC) holds promise for treating X-linked hyper-IgM Syndrome (HIGM1), but its actual therapeutic potential remains elusive. Here, we developed a one-size-fits-all editing strategy for effective T-cell correction, selection, and depletion and investigated the therapeutic potential of T-cell and HSPC therapies in the HIGM1 mouse model. Edited patients’ derived CD4 T cells restored physiologically regulated CD40L expression and contact-dependent B-cell helper function. Adoptive transfer of wild-type T cells into conditioned HIGM1 mice rescued antigen-specific IgG responses and protected mice from a disease-relevant pathogen. We then obtained ~ 25% CD40LG editing in long-term repopulating human HSPC. Transplanting such proportion of wild-type HSPC in HIGM1 mice rescued immune functions similarly to T-cell therapy. Overall, our findings suggest that autologous edited T cells can provide immediate and substantial benefits to HIGM1 patients and position T-cell ahead of HSPC gene therapy because of easier translation, lower safety concerns and potentially comparable clinical benefits.





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