Hematopoietic Tumors in a Mouse Model of X-linked Chronic Granulomatous Disease after Lentiviral Vector-Mediated Gene Therapy
Creators
- Jofra Hernández, Raisa1
- Calabria, Andrea1
- Sanvito, Francesca2
- De Mattia, Fabiola1
- Farinelli, Giada1
- Scala, Serena1
- Visigalli, Ilaria3
- Carriglio, Nicola3
- De Simone, Maura3
- Vezzoli, Michela3
- Cecere, Francesca3
- Migliavacca, Maddalena4
- Basso-Ricci, Luca1
- Omrani, Maryam1
- Benedicenti, Fabrizio1
- Norata, Rossana3
- Rancoita, Paola Maria Vittoria5
- Di Serio, Clelia5
- Albertini, Paola3
- Cristofori, Paola3
- Naldini, Luigi1
- Gentner, Bernhard1
- Montini, Eugenio1
- Aiuti, Alessandro1
- Mortellaro, Alessandra1
- 1. 1San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute
- 2. Pathology Unit, Department of Experimental Oncology, IRCCS San Raffaele Scientific Institute
- 3. GLP Test Facility, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute
- 4. Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute
- 5. University Centre for Statistics in the Biomedical Sciences, Vita-Salute San Raffaele University
Description
Chronic granulomatous disease (CGD) is a rare inherited disorder due to loss-of-function mutations in genes encoding the NADPH oxidase subunits. Hematopoietic stem and progenitor cell (HSPC) gene therapy (GT) using regulated lentiviral vectors (LVs) has emerged as a promising therapeutic option for CGD patients. We performed non-clinical Good Laboratory Practice (GLP) and laboratory-grade studies to assess the safety and genotoxicity of LV targeting myeloid specific Gp91phox expression in X-linked chronic granulomatous disease (XCGD) mice. We found persistence of gene-corrected cells for up to 1 year, restoration of Gp91phox expression and NADPH oxidase activity in XCGD phagocytes, and reduced tissue inflammation after LV-mediated HSPC GT.
Although most of the mice showed no hematological or biochemical toxicity, a small subset of XCGD GT mice developed
T cell lymphoblastic lymphoma (2.94%) and myeloid leukemia (5.88%). No hematological malignancies were identified in C57BL/6 mice transplanted with transduced XCGD HSPCs. Integration pattern analysis revealed an oligoclonal composition with rare dominant clones harboring vector insertions near oncogenes in mice with tumors. Collectively, our data support the long-term efficacy of LV-mediated HSPC GT in XCGD mice and provide a safety warning because the chronic inflammatory XCGD background may contribute to oncogenesis.
Files
Figura 3A_PB DHR granulocytes (right graph).csv
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