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Adenoviral-mediated gene transfer restores plasma ADAMTS13 antigen and activity in ADAMTS13 knockout mice

Gene Therapy volume 16, pages 1373–1379 (2009)Cite this article

Abstract

ADAMTS13 is a plasma metalloprotease that regulates the size of the von Willebrand factor (VWF) multimers. Genetic or acquired deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura (TTP) in humans. Plasma infusion is the treatment of choice for patients with congenital ADAMTS13 deficiency. However, this practice exposes patients to the risk of infections, allergies and fluid volume overload. The search for alternative treatments is required. Here, we tested the ability of systemically administered adenovirus encoding human ADAMTS13 to restore the deficient protein in the circulation of Adamts13−/− mice. Injection of the adenovirus efficiently transduced the liver, kidney, lung, heart and spleen, resulting in the secretion of ADAMTS13 into plasma. A reduced area of thrombi was observed when blood from Ad-ADAMTS13-treated mice was perfused over a collagen-coated surface in a parallel plate flow chamber compared with blood of Ad-βGal-treated controls. The secreted ADAMTS13 protein was functionally active even after 2 months from injection. The data provide the proof of principle for developing a novel therapy for the correction of ADAMTS13 deficiency in patients with hereditary TTP.

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Acknowledgements

We are grateful to Professor ZM Ruggeri (The Scripps Research Institute, La Jolla, CA, USA) for providing recombinant human VWF A1A2A3 domains and the anti-A3 domain monoclonal antibody. We are deeply indebted to Dr A Sonzogni for helping us with liver histological analysis. We also thank Dr Carla Zoja for her invaluable helpful discussion and criticism. Plasmids used for adenoviral construction and S8 cells are a kind gift from Novartis Pharma. The study is partially supported by a grant from the Istituto Superiore di Sanità, Roma, Italy. Piera Trionfini is a recipient of a fellowship from Fondazione Aiuti per la Ricerca sulle Malattie Rare (ARMR), Bergamo, Italy.

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Author notes

  1. P Trionfini and S Tomasoni: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Medicine, Mario Negri Institute for Pharmacological Research, Bergamo, Italy

    P Trionfini, S Tomasoni, M Galbusera, L Longaretti, D Corna, G Remuzzi & A Benigni

  2. Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA

    D Motto

  3. Unit of Nephrology and Dialysis, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo, Italy

    G Remuzzi

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  1. P Trionfini
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  2. S Tomasoni
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  3. M Galbusera
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  4. D Motto
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  5. L Longaretti
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  6. D Corna
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  7. G Remuzzi
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  8. A Benigni
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Correspondence to S Tomasoni.

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Supplementary Information accompanies the paper on Gene Therapy website (http://www.nature.com/gt)

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Trionfini, P., Tomasoni, S., Galbusera, M. et al. Adenoviral-mediated gene transfer restores plasma ADAMTS13 antigen and activity in ADAMTS13 knockout mice. Gene Ther 16, 1373–1379 (2009). https://doi.org/10.1038/gt.2009.98

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