Loading...
An experimental platform for systemic drug delivery to the retina.
Campbell, Matthew Nguyen, Anh T H Kiang, Anna-Sophia Tam, Lawrence C S Gobbo, Oliviero L Kerskens, Christian Ni Dhubhghaill, Sorcha Humphries, Marian M Farrar, G-Jane Kenna, Paul F
Campbell, Matthew
Nguyen, Anh T H
Kiang, Anna-Sophia
Tam, Lawrence C S
Gobbo, Oliviero L
Kerskens, Christian
Ni Dhubhghaill, Sorcha
Humphries, Marian M
Farrar, G-Jane
Kenna, Paul F
Advisors
Editors
Other Contributors
Date
2009-10-20
Date Submitted
Keywords
Other Subjects
Subject Mesh
Animals
Blood-Retinal Barrier
Calpain
Cysteine Proteinase Inhibitors
Disease Models, Animal
Drug Delivery Systems
Electroretinography
Guanosine Triphosphate
Humans
IMP Dehydrogenase
Magnetic Resonance Imaging
Membrane Proteins
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Oligopeptides
RNA Interference
RNA, Small Interfering
Retina
Retinitis Pigmentosa
Blood-Retinal Barrier
Calpain
Cysteine Proteinase Inhibitors
Disease Models, Animal
Drug Delivery Systems
Electroretinography
Guanosine Triphosphate
Humans
IMP Dehydrogenase
Magnetic Resonance Imaging
Membrane Proteins
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Oligopeptides
RNA Interference
RNA, Small Interfering
Retina
Retinitis Pigmentosa
Planned Date
Start Date
Collaborators
Principal Investigators
Files
Loading...
19822744.pdf
Adobe PDF, 1.56 MB
Alternative Titles
Publisher
Abstract
Degenerative retinopathies, including age-related macular degeneration, diabetic retinopathy, and hereditary retinal disorders--major causes of world blindness--are potentially treatable by using low-molecular 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.
Language
en
ISSN
1091-6490
eISSN
ISBN
DOI
10.1073/pnas.0908561106
PMID
19822744