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Reversible and Size-Selective Opening of the Inner Blood-Retina Barrier: A Novel Therapeutic Strategy

  • Matthew Campbell
  • Anh Thi Hong Nguyen
  • Anna-Sophia Kiang
  • Lawrence Tam
  • Paul F. Kenna
  • Sorcha Ni Dhubhghaill
  • Marian Humphries
  • G. Jane Farrar
  • Peter Humphries
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 664)

Abstract

The inner Blood-Retina-barrier (iBRB) remains a key element in retarding the development of novel therapeutics for the treatment of many ocular disorders. The iBRB contains tight-junctions (TJ’s) which reduce the space between adjacent endothelial cells lining the fine capillaries of the retinal microvasculature to form a selective and regulatable barrier. We have recently shown that in mice, the iBRB can be transiently and size-selectively opened to molecules with molecular weights of up to approximately 1 kDa using an siRNA-mediated approach involving suppression of the tight junction protein, claudin-5. We have systemically delivered siRNA targeting claudin-5 to retinal capillary endothelial cells in mice and through a series of tracer experiments and magnetic-resonance-imaging (MRI), we have shown a transient and size-selective increase in permeability at the iBRB to molecules below 1 kDa. The potential to exploit this specific compromise in iBRB integrity may have far reaching implications for the development of experimental animal models of retinal degenerative disorders, and for enhanced delivery of therapeutic molecules which would normally not traverse the iBRB. Using RNAi-mediated opening of the iBRB, the systemic delivery of low molecular weight therapeutics could in principle, hold real promise as an alternative to repeated intraocular inoculation of compounds. Results demonstrated here in mouse models, should lead to a ‘humanized’ form of systemic delivery as opposed to the hydrodynamic approach used in our work to date.

Keywords

Tight Junction Inner Nuclear Layer Blood Retinal Barrier Fine Capillary Adjacent Endothelial Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This work was supported by the Wellcome Trust, Fighting Blindness Ireland, and Science Foundation Ireland.

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Matthew Campbell
    • 1
  • Anh Thi Hong Nguyen
    • 1
  • Anna-Sophia Kiang
    • 1
  • Lawrence Tam
    • 1
  • Paul F. Kenna
    • 1
  • Sorcha Ni Dhubhghaill
    • 1
  • Marian Humphries
    • 1
  • G. Jane Farrar
    • 1
  • Peter Humphries
    • 1
  1. 1.Ocular Genetics Unit, Department of GeneticsTrinity College DublinDublin 2Ireland

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