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Matthew Campbell, Marian M. Humphries, Anna-Sophia Kiang, Anh T. Nguyen, Paul F. Kenna, Peter Humphries; AAV Mediated Systemic Low Molecular Weight Drug Delivery To The Retina. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4162.
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It has been estimated that up to 98% of systemically-deliverable low molecular weight anti-neovascular and neuroprotective drugs, many of which would have significant therapeutic potential in the treatment of degenerative retinal conditions, are prevented from entering the retina via the peripheral circulation because of the presence of the inner blood-retina barrier (iBRB). We have recently reported an experimental platform in rodents for non-invasive systemic drug delivery to the retina based on transient RNAi-mediated suppression of transcripts encoding claudin-5, a component of the tight junctions of the inner retinal vasculature. This process allows passive diffusion of clinically validated drugs from the peripheral circulation into the retina while excluding larger potentially harmful substances, and we have used it to radically improve vision in a range of animal models.
An AAV-2/9 vector was generated with a doxycycline inducible gene expressing claudin-5 shRNA. The system was tested via intra-vitreal and sub-retinal delivery routes and phenpotype assessments were made using electro-retinography (ERG) and magnetic resonance imaging (MRI).Extent of barrier modulation was assessed in animal models of wet AMD, and Retinitis pigmentosa and systemic delivery of anti-neovascular agents and neuro-protective agents was assessed.
We report herein on the use of barrier modulation in tandem with systemic drug therapy to prevent retinal degeneration in animal models of Retinitis pigmentoda (RP) and to suppress laser-induced-choroidal-neovascularisation (CNV). These observations constitute the basis of a minimally invasive systemic therapeutic modality for retinal diseases, including RP and AMD, where, in early stage disease, the iBRB is intact and impervious to systemically administered drugs.
AAV mediated modulation of the iBRB for the purposes of systemic drug delivery to the retina of low molecular weight drugs has the potential to radically improve the chronic treatment of the most common forms of retinal degeneration. Levels of active compound needed to produce a therapeutic effect can also be decreased significantly.
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