An experimental platform for systemic drug delivery to the retina

Abstract

Degenerative retinopathies, including age-related macular degeneration, diabetic retinopathy, and hereditary retinal disorders-major causes of world blindness-are potentially treatable by using lowmolecular weight neuroprotective, antiapoptotic, or antineovascular drugs. These agents are, however, not in current systemic use owing to, among other factors, their inability to passively diffuse across the microvasculature of the retina because of the presence of the inner blood-retina barrier (iBRB). Moreover, preclinical assessment of the efficacies of new formulations in the treatment of such conditions is similarly compromised. We describe here an experimental process for RNAi-mediated, size-selective, transient, and reversible modulation of the iBRB in mice to molecules up to 800 Da by suppression of transcripts encoding claudin-5, a protein component of the tight junctions of the inner retinal vasculature. MRI produced no evidence indicative of brain or retinal edema, and the process resulted in minimal disturbance of global transcriptional patterns analyzed in neuronal tissue. We show that visual function can be improved in IMPDH1 ؊/؊ mice, a model of autosomal recessive retinitis pigmentosa, and that the rate of photoreceptor cell death can be reduced in a model of light-induced retinal degeneration by systemic drug delivery after reversible barrier opening. These findings provide a platform for high-throughput drug screening in models of retinal degeneration, and they ultimately could result in the development of a novel ''humanized'' approach to therapy for conditions with little or no current forms of treatment.blood-retina barrier ͉ retinitis pigmentosa ͉ RNAi ͉ tight junctions ͉ claudin-5

Interleukin‐18 Has Antipermeablity and Antiangiogenic Activities in the Eye: Reciprocal Suppression With VEGF

“…Claudin 5 is a tight junction protein that plays a critical role in maintenance of the blood-brain barrier and blood-retinal barrier (Campbell et al, 2009; Nitta et al, 2003). Intracranial injection of VEGF causes blood-brain barrier breakdown and reduces claudin 5 staining in brain microvessels, and treatment of brain endothelial cell cultures with VEGF decreases expression of claudin 5 (Argaw et al, 2008).…”

Pharmacological Enhancement of ex vivo Gene Therapy Neuroprotection in a Rodent Model of Retinal Degeneration

“…Other work has focused on combining neuroprotectants [46][47][48] to improve efficacy. Other relevant investigations include efforts to improve drug penetration into retinal tissue [49] or the penetration of viral vectors or cells that could act as drug delivery devices [50] . An in- teresting approach has been to add neuroprotection to gene therapy for the underlying genetic abnormality [38] .…”

Targeted suppression of claudin-5 decreases cerebral oedema and improves cognitive outcome following traumatic brain injury

“…Using RNA interference targeting the tight junction component claudin-5, we show that the BBB can be modulated to enhance the exchange of very low molecular weight molecules of up to ~1 kDa for periods of between 24 apparent negative phenotypic or genotypic effects on experimental animals [15][16][17] . Claudin-5 has a key role in the formation of paracellular pores or channels that function in mediating selective ion permeability at the BBB 18,19 .…”