RNAi-mediated reversible opening of the blood-brain barrier
Article first published online: 28 MAY 2008
Copyright © 2008 John Wiley & Sons, Ltd.
The Journal of Gene Medicine
Volume 10, Issue 8, pages 930–947, August 2008
How to Cite
Campbell, M., Kiang, A.-S., Kenna, P. F., Kerskens, C., Blau, C., O'Dwyer, L., Tivnan, A., Kelly, J. A., Brankin, B., Farrar, G.-J. and Humphries, P. (2008), RNAi-mediated reversible opening of the blood-brain barrier. J. Gene Med., 10: 930–947. doi: 10.1002/jgm.1211
- Issue published online: 21 JUL 2008
- Article first published online: 28 MAY 2008
- Manuscript Accepted: 16 APR 2008
- Manuscript Revised: 15 APR 2008
- Manuscript Received: 13 NOV 2007
- Wellcome Trust
- Fighting Blindness Ireland
- European Union 5th Framework Programme. Grant Number: HPRN CT200000098
- European Union Evi-GenoRet. Grant Number: LSHG-CT-2005-512036
- European Union RETNET Project. Grant Number: MRTN-CT-2003-504003
- The British RP Society
- Health Research Board of Ireland
- Blood-brain barrier;
- tight junctions;
- RNA interference;
- drug delivery
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.
Using a hydrodynamic approach, we delivered siRNA targeting the TJ protein claudin-5 to the endothelial cells of the BBB in mice.
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.
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.