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RNAi‐mediated reversible opening of the blood‐brain barrier
Author(s) -
Campbell Matthew,
Kiang AnnaSophia,
Kenna Paul F.,
Kerskens Christian,
Blau Christoph,
O'Dwyer Laurence,
Tivnan Amanda,
Kelly Julie Anne,
Brankin Brenda,
Farrar GwynethJane,
Humphries Peter
Publication year - 2008
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.1211
Subject(s) - blood–brain barrier , tight junction , chemistry , microbiology and biotechnology , in vitro , drug delivery to the brain , in vivo , pharmacology , biophysics , medicine , biology , neuroscience , central nervous system , biochemistry
Abstract Background The blood‐brain barrier (BBB) contains tight junctions (TJs) which reduce the space between adjacent endothelial cells lining the fine capillaries of the microvasculature of the brain to form a selective and regulatable barrier. Methods Using a hydrodynamic approach, we delivered siRNA targeting the TJ protein claudin‐5 to the endothelial cells of the BBB in mice. Results We have shown a significant decrease in claudin‐5 mRNA levels 24 and 48 hours post‐delivery of siRNA, with levels of protein expression decreasing up to 48 hours post‐injection compared to uninjected, phosphate‐buffered saline (PBS)‐injected and non‐targeting siRNA‐injected mice. We observed increased permeability at the BBB to molecules up to 742 Da, but not 4400 Da, using tracer molecule perfusion and MRI analysis. To illustrate the functional efficacy of size‐selective and transient barrier opening, we have shown that enhanced delivery of the small neuropeptide thyrotropin‐releasing hormone (TRH) (MW 360 Da) to the brains of mice 48 hours post‐injection of siRNA targeting claudin‐5 significantly modifies behavioural output. Conclusions These data demonstrate that it is now possible to transiently and size‐selectively open the BBB in mice, allowing in principle the delivery of a wide range of agents for the establishment and treatment of experimental mouse models of neurodegenerative, neuropsychiatric and malignant diseases. Copyright © 2008 John Wiley & Sons, Ltd.