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Hematopoietic gene therapy restores thymidine phosphorylase activity in a cell culture and a murine model of MNGIE

Gene Therapy volume 18, pages 795–806 (2011)Cite this article

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Abstract

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the TYMP gene, which encodes thymidine phosphorylase (TP). TP dysfunction results in systemic thymidine (dThd) and deoxyuridine (dUrd) overload, which selectively impair mitochondrial DNA replication. Allogeneic hematopoietic transplantation has been used to treat MNGIE patients; however, this approach has serious adverse effects, including the toxicity of myeloablative conditioning, graft rejection and graft-versus-host disease. With the aim of testing the feasibility of gene therapy for MNGIE, we transduced TP-deficient B-lymphoblastoid cells from two MNGIE patients, with lentiviral vectors carrying a functional copy of the human TYMP DNA coding sequence. This restored TP activity in the cells, which reduced the excretion of dThd and dUrd and their concentrations when added in excess. Additionally, lentiviral-mediated hematopoietic gene therapy was used in partially myeloablated double Tymp/Upp1 knockout mice. In spite of the relatively low levels of molecular chimerism achieved, high levels of TP activity were observed in the peripheral blood of the transplanted mice, with a concomitant reduction of nucleoside concentrations. Our results suggest that hematopoietic gene therapy could be an alternative treatment for this devastating disorder in the future.

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Acknowledgements

We would like to thank Luigi Naldini for kindly providing the lentiviral vectors p305 and p-sham, and Michael Terry for his English Language assistance. This work was supported by the Spanish Instituto de Salud Carlos III [PI 06/0735, PS09/01591, Miguel Servet grants to JB and RM] and the United Mitochondrial Disease Foundation [UMDF 04/042].

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Author notes

  1. H Eixarch & L Palenzuela

    Present address: 6Current address: Centre d'Esclerosi Múltiple de Catalunya, Unitat de Neuroimmunologia Clínica (HE) and Servei de Medicina Interna-Hepatologia (LP), Institut de Recerca Hospital Universitari Vall d'Hebron, Barcelona, Spain.,

Authors and Affiliations

  1. Laboratori of Neuromuscular and Mitochondrial Disorders, Institut de Recerca Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

    J Torres-Torronteras, L Palenzuela, A L Andreu & R Martí

  2. Biomedical Network Research Centre on Rare Diseases (CIBERER) ISCIII, Spain

    J Torres-Torronteras, L Palenzuela, A L Andreu & R Martí

  3. Banc de Sang i Teixits, Institut de Recerca Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

    A Gómez, H Eixarch & J Barquinero

  4. Department of Drug Development, Nevada Cancer Institute, Las Vegas, NV, USA

    G Pizzorno

  5. Department of Neurology, Columbia University Medical Center, New York, NY, USA

    M Hirano

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  1. J Torres-Torronteras
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Correspondence to R Martí.

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Torres-Torronteras, J., Gómez, A., Eixarch, H. et al. Hematopoietic gene therapy restores thymidine phosphorylase activity in a cell culture and a murine model of MNGIE. Gene Ther 18, 795–806 (2011). https://doi.org/10.1038/gt.2011.24

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