An experimental platform for systemic drug delivery to the retina.
Nguyen, Anh T H
Tam, Lawrence C S
Gobbo, Oliviero L
Ni Dhubhghaill, Sorcha
Humphries, Marian M
Kenna, Paul F
AffiliationOcular Genetics Unit, Department of Genetics, Trinity College Dublin, Dublin 2, Ireland. firstname.lastname@example.org
Cysteine Proteinase Inhibitors
Disease Models, Animal
Drug Delivery Systems
Magnetic Resonance Imaging
Mice, Inbred BALB C
Mice, Inbred C57BL
RNA, Small Interfering
MetadataShow full item record
CitationAn experimental platform for systemic drug delivery to the retina. 2009, 106 (42):17817-22 Proc. Natl. Acad. Sci. U.S.A.
JournalProceedings of the National Academy of Sciences of the United States of America
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.
- Reversible and size-selective opening of the inner Blood-Retina barrier: a novel therapeutic strategy.
- Authors: Campbell M, Nguyen AT, Kiang AS, Tam L, Kenna PF, Dhubhghaill SN, Humphries M, Farrar GJ, Humphries P
- Issue date: 2010
- Systemic low-molecular weight drug delivery to pre-selected neuronal regions.
- Authors: Campbell M, Humphries MM, Kiang AS, Nguyen AT, Gobbo OL, Tam LC, Suzuki M, Hanrahan F, Ozaki E, Farrar GJ, Kenna PF, Humphries P
- Issue date: 2011 Apr
- On the molecular pathology of neurodegeneration in IMPDH1-based retinitis pigmentosa.
- Authors: Aherne A, Kennan A, Kenna PF, McNally N, Lloyd DG, Alberts IL, Kiang AS, Humphries MM, Ayuso C, Engel PC, Gu JJ, Mitchell BS, Farrar GJ, Humphries P
- Issue date: 2004 Mar 15
- Barrier modulation in drug delivery to the retina.
- Authors: Campbell M, Humphries MM, Humphries P
- Issue date: 2013
- Therapeutic benefit derived from RNAi-mediated ablation of IMPDH1 transcripts in a murine model of autosomal dominant retinitis pigmentosa (RP10).
- Authors: Tam LC, Kiang AS, Kennan A, Kenna PF, Chadderton N, Ader M, Palfi A, Aherne A, Ayuso C, Campbell M, Reynolds A, McKee A, Humphries MM, Farrar GJ, Humphries P
- Issue date: 2008 Jul 15