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A nanomedicine to treat ocular surface inflammation: performance on an experimental dry eye murine model

Gene Therapy volume 20, pages 467–477 (2013)Cite this article

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Abstract

MUC5AC is a glycoprotein with gel-forming properties, whose altered expression has been implicated in the pathogenesis of dry eye disease. The aim of our study was to achieve an efficient in vivo transfection of MUC5AC, restore its normal levels in an inflamed ocular surface and determine whether restored MUC5AC levels improve ocular surface inflammation. Cationized gelatin-based nanoparticles (NPs) loaded with a plasmid coding a modified MUC5AC protein (pMUC5AC) were instilled in healthy and experimental dry eye (EDE) mice. MUC5AC expression, clinical signs, corneal fluorescein staining and tear production were evaluated. Ocular specimens were processed for histopathologic evaluation, including goblet cell count and CD4 immunostaining. Neither ocular discomfort nor irritation was observed in vivo after NP treatment. Expression of modified MUC5AC was significantly higher in ocular surface tissue of pMUC5AC-NP-treated animals than that of controls. In healthy mice, pMUC5AC-NPs had no effect on fluorescein staining or tear production. In EDE mice, both parameters significantly improved after pMUC5AC-NP treatment. Anterior eye segment of treated mice showed normal architecture and morphology with lack of remarkable inflammatory changes, and a decrease in CD4+ T-cell infiltration. Thus, pMUC5AC-NPs were well tolerated and able to induce the expression of modified MUC5A in ocular surface tissue, leading to reduction of the inflammation and, consequently improving the associated clinical parameters, such as tear production and fluorescein staining. These results identify a potential application of pMUC5AC-NPs as a new therapeutic modality for the treatment of dry eye disease.

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Acknowledgements

We thank Michael E Stern, PhD, (Allergan Inc., CA, USA) for kindly providing facilities for animal experiments and for expert advice; Sagrario Callejo, PhD, and the Confocal Microscopy Service from the University of Valladolid, for their technical support; Amalia Enriquez de Salamanca, PhD, and Maria Jesus Benito, MSc, for technical support in Luminex experiments; and Itziar Fernandez, MSc, for statistical analysis advice. This work was supported by grants from the Spanish Ministry of Science and Technology (MAT2007-64626-C01-01/C02-02 and FPU Scholarship Program), and Programme AlBan, the European Union Programme of High Level Scholarships for Latin America (scholarship no. E07D402978BR).

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Author notes

  1. L Contreras-Ruiz and G K Zorzi: These authors contributed equally to the work.

Authors and Affiliations

  1. Ocular Surface Group-IOBA, University of Valladolid, Valladolid, Spain

    L Contreras-Ruiz, D Hileeto, A López-García, M Calonge & Y Diebold

  2. Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER BBN), Valladolid, Spain

    L Contreras-Ruiz, A López-García, M Calonge & Y Diebold

  3. Department of Pharmaceutical Technology, NANOBIOFAR Group, University of Santiago de Compostela, Santiago de Compostela, Spain

    G K Zorzi, B Seijo & A Sánchez

  4. Molecular Imagen Group, IDIS, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain

    B Seijo & A Sánchez

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  1. L Contreras-Ruiz
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  2. G K Zorzi
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Correspondence to Y Diebold.

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Contreras-Ruiz, L., Zorzi, G., Hileeto, D. et al. A nanomedicine to treat ocular surface inflammation: performance on an experimental dry eye murine model. Gene Ther 20, 467–477 (2013). https://doi.org/10.1038/gt.2012.56

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  • DOI: https://doi.org/10.1038/gt.2012.56

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