Journal Article

Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome

Scaramuzza, Samantha, Ferrua, Francesca, Naldini, Luigi, Gardner, Jason, Galimberti, Stefania, Ciceri, Fabio, Neduva, Victor, Von Kalle, Christof, Giannelli, Stefania, Assanelli, Andrea, Pellin, Danilo, Biasco, Luca, Calabria, Andrea, Biffi, Alessandra, Baricordi, Cristina, Finocchi, Andrea, Banerjee, Pinaki P., Schmidt, Manfred, Di Nunzio, Sara, Castiello, Maria Carmina, Mehta, Nalini, Villa, Anna, Casiraghi, Miriam, Callegaro, Luciano, Galy, Anne, Evangelio, Costanza, Orange, Jordan S., Rizzardi, Paolo, Dionisio, Francesca, Roncarolo, Maria Grazia, Benati, Claudia, Aiuti, Alessandro, Valsecchi, Maria Grazia, Bosticardo, Marita, Metin, Ayse, Miniero, Roberto, Di Serio, Clelia, Dow, David J., Montini, Eugenio, Cicalese, Maria Pia

2013

Overview

Few disciplines in contemporary clinical research have experienced the high expectations directed at the gene therapy field. However, gene therapy has been challenging to translate to the clinic, often because the therapeutic gene is expressed at insufficient levels in the patient or because the gene delivery vector integrates near protooncogenes, which can cause leukemia (see the Perspective by Verma ). Biffi et al. ( 1233158 , published online 11 July) and Aiuti et al. ( 1233151 ; published online 11 July) report progress on both fronts in gene therapy trials of three patients with metachromatic leukodystrophy (MLD), a neurodegenerative disorder, and three patients with Wiskott-Aldrich syndrome (WAS), an immunodeficiency disorder. Optimized lentiviral vectors were used to introduce functional MLD or WAS genes into the patients' hematopoietic stem cells (HSCs) ex vivo, and the transduced cells were then infused back into the patients, who were then monitored for up to 2 years. In both trials, the patients showed stable engraftment of the transduced HSC and high expression levels of functional MLD or WAS genes. Encouragingly, there was no evidence of lentiviral vector integration near proto-oncogenes, and the gene therapy treatment halted disease progression in most patients. A longer follow-up period will be needed to further validate efficacy and safety. Lentivirus-mediated gene therapy produces encouraging results in three children with a rare immunodeficiency disorder. [Also see Perspective by Verma ] 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 reinfused the cells after a reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical scores. Vector integration analyses revealed highly polyclonal and multilineage 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 to 32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science,American Association for the Advancement of Science (AAAS)
• Subject: Bone marrow / Child / disease course / Disorders / Gene therapy / gene transfer / Genes / Genetic Therapy - methods / Genetic Vectors / Hematology / Hematopoietic Stem Cell Transplantation / hematopoietic stem cells / Hematopoietic Stem Cells - metabolism / Humans / immunosuppression / Lentivirus / Leukemia / Life Sciences / Male / Mathematical analysis / neurodegenerative diseases / Online / Patients / proto-oncogenes / RESEARCH ARTICLE SUMMARY / Safety / Skin diseases / Stem cells / Transduction, Genetic / Vectors (mathematics) / Verma / Virus Integration / Wiskott-Aldrich Syndrome - therapy / Wiskott-Aldrich Syndrome Protein - genetics