Reversible and size-selective opening of the inner Blood-Retina barrier: a novel therapeutic strategy.
The inner Blood-Retina-barrier (iBRB) remains a key element in retarding the development of novel therapeutics for the treatment of many ocular disorders. The iBRB contains tight-junctions (TJ's) which reduce the space between adjacent endothelial cells lining the fine capillaries of the retinal microvasculature to form a selective and regulatable barrier. We have recently shown that in mice, the iBRB can be transiently and size-selectively opened to molecules with molecular weights of up to approximately 1 kDa using an siRNA-mediated approach involving suppression of the tight junction protein, claudin-5. We have systemically delivered siRNA targeting claudin-5 to retinal capillary endothelial cells in mice and through a series of tracer experiments and magnetic-resonance-imaging (MRI), we have shown a transient and size-selective increase in permeability at the iBRB to molecules below 1 kDa. The potential to exploit this specific compromise in iBRB integrity may have far reaching implications for the development of experimental animal models of retinal degenerative disorders, and for enhanced delivery of therapeutic molecules which would normally not traverse the iBRB. Using RNAi-mediated opening of the iBRB, the systemic delivery of low molecular weight therapeutics could in principle, hold real promise as an alternative to repeated intraocular inoculation of compounds. Results demonstrated here in mouse models, should lead to a 'humanized' form of systemic delivery as opposed to the hydrodynamic approach used in our work to date.
Campbell
Matthew
M
Department of Genetics, Trinity College Dublin, Dublin 2, Ireland. matthew.campbell@tcd.ie
Nguyen
Anh Thi Hong
AT
Kiang
Anna-Sophia
AS
Tam
Lawrence
L
Kenna
Paul F
PF
Dhubhghaill
Sorcha Ni
SN
Humphries
Marian
M
Farrar
G Jane
GJ
Humphries
Peter
P
D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism; D001813:Blood-Retinal Barrier / Q000378:metabolism*; D062507:Claudin-5; D016616:Cryoultramicrotomy; D005119:Extravasation of Diagnostic and Therapeutic Materials; D005128:Eye Diseases / Q000628:therapy*; D019786:Gadolinium DTPA / Q000378:metabolism; D007267:Injections; D008279:Magnetic Resonance Imaging; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D010477:Perfusion; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
D001562:Benzimidazoles; D062507:Claudin-5; C491511:Cldn5 protein, mouse; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D019786:Gadolinium DTPA; C017807:bisbenzimide ethoxide trihydrochloride