An experimental platform for systemic drug delivery to the retina.

Hdl Handle:
http://hdl.handle.net/10147/93898
Title:
An experimental platform for systemic drug delivery to the retina.
Authors:
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; Humphries, Peter
Affiliation:
Ocular Genetics Unit, Department of Genetics, Trinity College Dublin, Dublin 2, Ireland. matthew.campbell@tcd.ie
Citation:
An experimental platform for systemic drug delivery to the retina. 2009, 106 (42):17817-22 Proc. Natl. Acad. Sci. U.S.A.
Journal:
Proceedings of the National Academy of Sciences of the United States of America
Issue Date:
20-Oct-2009
URI:
http://hdl.handle.net/10147/93898
DOI:
10.1073/pnas.0908561106
PubMed ID:
19822744
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
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
ISSN:
1091-6490

Full metadata record

DC FieldValue Language
dc.contributor.authorCampbell, Matthewen
dc.contributor.authorNguyen, Anh T Hen
dc.contributor.authorKiang, Anna-Sophiaen
dc.contributor.authorTam, Lawrence C Sen
dc.contributor.authorGobbo, Oliviero Len
dc.contributor.authorKerskens, Christianen
dc.contributor.authorNi Dhubhghaill, Sorchaen
dc.contributor.authorHumphries, Marian Men
dc.contributor.authorFarrar, G-Janeen
dc.contributor.authorKenna, Paul Fen
dc.contributor.authorHumphries, Peteren
dc.date.accessioned2010-03-08T16:45:33Z-
dc.date.available2010-03-08T16:45:33Z-
dc.date.issued2009-10-20-
dc.identifier.citationAn experimental platform for systemic drug delivery to the retina. 2009, 106 (42):17817-22 Proc. Natl. Acad. Sci. U.S.A.en
dc.identifier.issn1091-6490-
dc.identifier.pmid19822744-
dc.identifier.doi10.1073/pnas.0908561106-
dc.identifier.urihttp://hdl.handle.net/10147/93898-
dc.description.abstractDegenerative 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.-
dc.language.isoenen
dc.subject.meshAnimals-
dc.subject.meshBlood-Retinal Barrier-
dc.subject.meshCalpain-
dc.subject.meshCysteine Proteinase Inhibitors-
dc.subject.meshDisease Models, Animal-
dc.subject.meshDrug Delivery Systems-
dc.subject.meshElectroretinography-
dc.subject.meshGuanosine Triphosphate-
dc.subject.meshHumans-
dc.subject.meshIMP Dehydrogenase-
dc.subject.meshMagnetic Resonance Imaging-
dc.subject.meshMembrane Proteins-
dc.subject.meshMice-
dc.subject.meshMice, Inbred BALB C-
dc.subject.meshMice, Inbred C57BL-
dc.subject.meshMice, Knockout-
dc.subject.meshOligopeptides-
dc.subject.meshRNA Interference-
dc.subject.meshRNA, Small Interfering-
dc.subject.meshRetina-
dc.subject.meshRetinitis Pigmentosa-
dc.titleAn experimental platform for systemic drug delivery to the retina.en
dc.contributor.departmentOcular Genetics Unit, Department of Genetics, Trinity College Dublin, Dublin 2, Ireland. matthew.campbell@tcd.ieen
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of Americaen

Related articles on PubMed

All Items in Lenus, The Irish Health Repository are protected by copyright, with all rights reserved, unless otherwise indicated.