EMBO Molecular Medicine (Mar 2021)

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

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

DOI
https://doi.org/10.15252/emmm.202013545
Journal volume & issue
Vol. 13, no. 3
pp. n/a – n/a

Abstract

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Abstract 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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