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Exonic knockout and knockin gene editing in hematopoietic stem and progenitor cells rescues RAG1 immunodeficiency

Castiello, Maria Carmina, Brandas, Chiara, Ferrari, Samuele, Porcellini, Simona, Sacchetti, Nicolò, Canarutto, Daniele, Draghici, Elena, Merelli, Ivan, Barcella, Matteo, Pelosi, Gabriele, Vavassori, Valentina, Varesi, Angelica, Jacob, Aurelien, Scala, Serena, Basso Ricci, Luca, Paulis, Marianna, Strina, Dario, Di Verniere, Martina, Sergi Sergi, Lucia, Serafini, Marta, Holland, Steven M., Bergerson, Jenna R. E., De Ravin, Suk See, Malech, Harry L., Pala, Francesca, Bosticardo, Marita, Brombin, Chiara, Cugnata, Federica, Calzoni, Enrica, Crooks, Gay M., Notarangelo, Luigi D., Genovese, Pietro, Naldini, Luigi, Villa, Anna·2024·Science Translational Medicine
DOI 10.1126/scitranslmed.adh8162
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Abstract

Recombination activating genes ( RAGs ) are tightly regulated during lymphoid differentiation, and their mutations cause a spectrum of severe immunological disorders. Hematopoietic stem and progenitor cell (HSPC) transplantation is the treatment of choice but is limited by donor availability and toxicity. To overcome these issues, we developed gene editing strategies targeting a corrective sequence into the human RAG1 gene by homology-directed repair (HDR) and validated them by tailored two-dimensional, three-dimensional, and in vivo xenotransplant platforms to assess rescue of expression and function. Whereas integration into intron 1 of RAG1 achieved suboptimal correction, in-frame insertion into exon 2 drove physiologic human RAG1 expression and activity, allowing disruption of the dominant-negative effects of unrepaired hypomorphic alleles. Enhanced HDR-mediated gene editing enabled the correction of human RAG1 in HSPCs from patients with hypomorphic RAG1 mutations to overcome T and B cell differentiation blocks. Gene correction efficiency exceeded the minimal proportion of functional HSPCs required to rescue immunodeficiency in Rag1 –/– mice, supporting the clinical translation of HSPC gene editing for the treatment of RAG1 deficiency.

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Cited by

Metadata

Authors
Castiello, M. C., Brandas, C., Ferrari, S., Porcellini, S., Sacchetti, N., Canarutto, D., Draghici, E., Merelli, I., Barcella, M., Pelosi, G., Vavassori, V., Varesi, A., Jacob, A., Scala, S., Basso Ricci, L., Paulis, M., Strina, D., Di Verniere, M., Sergi Sergi, L., Serafini, M., Holland, S. M., Bergerson, J. R. E., De Ravin, S. S., Malech, H. L., Pala, F., Bosticardo, M., Brombin, C., Cugnata, F., Calzoni, E., Crooks, G. M., Notarangelo, L. D., Genovese, P., Naldini, L., & Villa, A.
Affiliations
  • San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget), IRCSS San Raffaele Scientific Institute, Milan 20132, Italy.
  • Milan Unit, Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Rozzano (MI) 20089, Italy.
  • Translational and Molecular Medicine (DIMET), University of Milano-Bicocca, Monza 20900, Italy.
  • Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD 20892, USA.
  • University Center for Statistics in the Biomedical Sciences, Vita-Salute San Raffaele University, Milan 20132, Italy.
  • Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
ORCID
Venue
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Published
2024-02-07
Volume
16
Issue
733
ISSN
  • 1946-6234
  • 1946-6242
DOI
10.1126/scitranslmed.adh8162
Cited by
25
References
9
Language
en

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