Lentivirus-based Gene Therapy of Hematopoietic Stem Cells in Wiskott-Aldrich Syndrome

Wiskott-Aldrich Syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative but, when matched donors are unavailable, infusion of autologous HSPCs modified...

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Published in:Science (American Association for the Advancement of Science) 2013-07, Vol.341 (6148), p.1233151-1233151
Main Authors: Aiuti, Alessandro, Biasco, Luca, Scaramuzza, Samantha, Ferrua, Francesca, Cicalese, Maria Pia, Baricordi, Cristina, Dionisio, Francesca, Calabria, Andrea, Giannelli, Stefania, Castiello, Maria Carmina, Bosticardo, Marita, Evangelio, Costanza, Assanelli, Andrea, Casiraghi, Miriam, Di Nunzio, Sara, Callegaro, Luciano, Benati, Claudia, Rizzardi, Paolo, Pellin, Danilo, Di Serio, Clelia, Schmidt, Manfred, Von Kalle, Christof, Gardner, Jason, Mehta, Nalini, Neduva, Victor, Dow, David J., Galy, Anne, Miniero, Roberto, Finocchi, Andrea, Metin, Ayse, Banerjee, Pinaki, Orange, Jordan, Galimberti, Stefania, Valsecchi, Maria Grazia, Biffi, Alessandra, Montini, Eugenio, Villa, Anna, Ciceri, Fabio, Roncarolo, Maria Grazia, Naldini, Luigi
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Language:English
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Summary:Wiskott-Aldrich Syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative but, when matched donors are unavailable, infusion of autologous HSPCs modified ex vivo by gene therapy is an alternative approach. We used a lentiviral vector encoding functional WASP to genetically correct HSPCs from three WAS patients and re-infused the cells after reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical score. Vector integration analyses revealed highly polyclonal and multi-lineage haematopoiesis resulting from the gene corrected HSPCs. Lentiviral gene therapy did not induce selection of integrations near oncogenes and no aberrant clonal expansion was observed after 20–32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1233151