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Front. Immunol. | doi: 10.3389/fimmu.2018.02703


Diana Carranza1,  Sara Torres-Rusillo1*, Gloria Ceballos-Pérez1, Eva Blanco-Jiménez2, Martin Muñoz-López2,  Jose L. Garcia-Perez2 and  Ignacio J. Molina1
  • 1Universidad de Granada, Spain
  • 2Junta de Andalucía de Genómica e Investigación Oncológica (GENYO), Spain

Ataxia-telangiectasia (A-T) is a complex disease arising from mutations in the ATM gene (Ataxia-Telangiectasia Mutated), which plays crucial roles in repairing double-strand DNA breaks (DSBs). Heterogeneous immunodeficiency, extreme radiosensitivity, frequent appearance of tumors and neurological degeneration are hallmarks of the disease, which carries high morbidity and mortality because only palliative treatments are currently available. Gene therapy was effective in animal models of the disease, but the large size of the ATM cDNA required the use of HSV-1 or HSV/AAV hybrid amplicon vectors, whose characteristics make them unlikely tools for treating A-T patients.
Due to recent advances in vector packaging, production and biosafety, we developed a lentiviral vector containing the ATM cDNA and tested whether or not it could rescue cellular defects of A-T human mutant fibroblasts. Although the cargo capacity of lentiviral vectors is an inherent limitation in their use, and despite the large size of the transgene, we successfully transduced around 20% of ATM-mutant cells. ATM expression and phosphorylation assays indicated that the neoprotein was functional in transduced cells, further reinforced by their restored capacity to phosphorylate direct ATM substrates such as p53 and their capability to repair radiation-induced DSBs. In addition, transduced cells also restored cellular radiosensitivity and cell cycle abnormalities. Our results demonstrate that lentiviral vectors can be used to rescue the intrinsic cellular defects of ATM-mutant cells, which represent, in spite of their limitations, a proof-of-concept for A-T gene therapy.

Keywords: Ataxia-telangiectasia (AT), Gene Therapy, lentiviral (LV) vector, Monogenic diseases, cell reconstitution

Received: 02 Aug 2018; Accepted: 01 Nov 2018.

Edited by:

Fabio Candotti, Lausanne University Hospital (CHUV), Switzerland

Reviewed by:

Claire Booth, Great Ormond Street Institute of Child Health, University College London, United Kingdom
Ruben Martinez-Barricarte, Rockefeller University, United States  

Copyright: © 2018 Carranza, Torres-Rusillo, Ceballos-Pérez, Blanco-Jiménez, Muñoz-López, Garcia-Perez and Molina. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Sara Torres-Rusillo, Universidad de Granada, Granada, 18071, Spain,