On the development of molecular approaches to therapy for retinitis pigmentosa

Abstract

Endothelial cells lining the microvasculature of the retina have highly evolved “tight junctions” reducing the space between adjacent cells to form a selective and highly regulatable barrier called the inner blood-retina barrier (iBRB). While many degenerative retinopathies are potentially treatable using available low molecular weight drugs, an estimated 98% of these cannot diffuse passively across the iBRB (Pardridge, 2007). In addition, intra-ocular injection of therapeutic agents is widely used experimentally in rodent models of retinal degeneration, however regular intravitreal injections in humans poses a low, but significant risk of severe endophthalmitis, haemorrhage, or detachment of the retina and is not a realistic option for repeated administration. Using an RNAi approach, hydrodynamic injection in mice of siRNA targeting the tight junction protein claudin-5 results in a transient opening of the iBRB to molecules of up to 1 kDa for a period of between 24 and 72 hours post injection (Campbell et al., 2009, Campbell el al., 2010). Subretinal inoculation of AAV2/9 expressing a doxycycline-inducible shRNA targeting claudin-5 (CLDN5 AAV2/9) results in a similar barrier modulation for the period of time during which the inducing agent doxycycline is administered, providing a means of systemic drug delivery specifically to the retina and avoiding systemic access to the brain (Campbell et al., 2011).