On further development of barrier modulation as a technique for systemic ocular drug delivery

Abstract

Many systemically deliverable low-molecular-weight drugs with proven efficacy as neuroprotective, anti-inflammatory, anti-neovascular, cytotoxic, or anti-microbial agents are blocked from entering the eye by the inner blood-retina barrier. Recent reports from this laboratory have shown that it is possible to modulate the iBRB reversibly in mice by systemic administration of siRNA targeting transcripts derived from claudin 5, a tight junction protein of the endothelial cells lining the inner retinal microvasculature, rendering the iBRB transiently permeable to compounds up to approximately 1,000 Da in molecular weight. The system has been validated by demonstrating improved visual function in a model of autosomal recessive retinitis pigmentosa (IMPDH1-/- mice) and by suppression of light-induced damage to the retina, in each case by systemic drug delivery following barrier modulation. In this review, we explore how this technique could be improved by the down-regulation of transcripts encoding other tight junction endothelial proteins, particularly ones which would enable outer blood-retina barrier modulation. © 2012 Springer Science+Business Media, LLC.