April 2009
Volume 50, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2009
Novel Approaches for the Treatment of Retinitis Pigmentosa (RP); Enhanced Systemic Delivery of Therapeutics
Author Affiliations & Notes
  • M. Campbell
    Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
  • A.-S. Kiang
    Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
  • P. F. Kenna
    Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
  • M. Humphries
    Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
  • P. Humphries
    Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
Investigative Ophthalmology & Visual Science April 2009, Vol.50, 3885. doi:
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    • Get Citation

      M. Campbell, A.-S. Kiang, P. F. Kenna, M. Humphries, P. Humphries; Novel Approaches for the Treatment of Retinitis Pigmentosa (RP); Enhanced Systemic Delivery of Therapeutics. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3885.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Delivery of a large range of potentially therapeutic compounds to the inner retina is impeded by the presence of the inner blood-retina barrier (iBRB). The fine microvasculature of the inner retina is lined with endothelial cells which contain "tight junctions" (TJ’s), limiting the passage of molecules across the paracellular pathway and forming a selective and highly regulateable barrier. Here, we describe a novel method for size-selectively modulating the iBRB by suppression of the TJ component claudin-5 using an RNAi-approach in mice. Moreover, we now show that guanosine-triphosphate (GTP), a central mediator of the visual phototransduction cascade can be delivered systemically in IMPDH-/- mice, a model lacking the rate limiting enzyme for the de novo synthesis of GTP. These mice develop a mild retinopathy and display a decreased electoretinogram (ERG) response in older age.

Methods: : Using a hydrodynamic approach, we have delivered siRNA targeting claudin-5 to the retinal microvasculature of IMPDH-/- mice over 11 months of age. We have assessed claudin-5 levels in the retina using Western blot, RT-PCR and Immunohistochemistry analyses. Subsequent to this, and when maximum iBRB modulation has occurred, we have delivered guanosine triphosphate systemically immediately prior to ERG measurements

Results: : IMPDH-/- mice with compromised ERG responses over 11 months of age appear to gain functional increases in ERG following enhanced delivery of GTP when compared to mice receiving no iBRB modulation.

Conclusions: : These findings, while further validating RNAi-mediated opening of the iBRB as a novel therapeutic approach may have profound implications for the treatment of RP and indeed other degenerative retinal conditions. Moreover, development of an inducible adeno-associated viral vector method of suppressing claudin-5 locally could potentially "humanize" this form of treatment, combining gene therapy with a pharmacological approach.

Keywords: RNAi • retina • cell adhesions/cell junctions 
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