RNAi-mediated Blood Brain and Blood retina Barrier modulation - PH01-112-01

A novel method for modulating tight junction proteins to transiently, reversibly, and size-selectively open the blood brain barrier (BBB) and blood retinal barrier (BRB)

Technology Overview:
Many attempts have been made either to break the blood-brain barrier (BBB) or to design delivery systems that enable pharmacological agents to traverse the endothelial cells of brain capillaries. However, such attempts have been made without due consideration given to the structure of the tight junctions (TJs), which reduce the space between the plasma membranes of contacting endothelial cells to form a selective and highly regulatable barrier.

Researchers at Trinity College Dublin have developed a novel platform technology that employs the use of interfering RNA (siRNA) to target tight junction proteins that are present at the BBB and BRB, such as claudins, occudins and zona occludens. Targeting TJ proteins induces both a transient and size-selective increase in permeability of the BBB and BRB, thus allowing for the delivery of small therapeutic molecules which would otherwise be excluded from the brain and retina if delivered systemically.

The technology is a platform technology such that it can be used for controlled delivery of therapeutic agents that are typically blocked by the BBB and BRB, thus having far reaching implications in the area of neurology, ophthalmology and drug delivery in general.
The technology can be applied to experimental animal models of neurodegenerative and neuropsychiatric diseases, for therapeutic applications involving drug delivery/drug screening in mice with xenografted or spontaneously occurring brain tumours, and for advancing the understanding of BBB function in general.
The technology can be directly used for the treatment of Stroke and Traumatic Brain Injury by facilitating the decrease in cerebral oedema. For this application, modulating the BBB to allow water diffusion from the brain would occur for a significantly longer period of time than the current treatment, mannitol, which only lasts for up to 24hrs.
The technology is transient and reversible which is essential for controlled drug delivery and ensuring that the the BBB and BRB are not completely broken down, compromising brain function in general.

Development Stage:
Efficacy of technology has been demonstrated in vivo, whereby the Researchers have demonstrated the ability of the BBB to become permeable to molecules of up to 800 daltons, observed using tracer molecule perfusion and MRI analysis. The researchers are now in the process of developing an inducible system, whereby adeno-associated virus (AAV) expressing shRNA targeting claudin-5 can be inoculated in specific regions of the brain or indeed the retina, to cause 'site-specific' opening of the BBB/BRB.

Principal Inventors: Prof. Peter Humphries, Dr. Matthew Campbell and Dr. Anna-Sophie Kiang

Publications: Campbell et al., 2008. RNAi-mediated reversible opening of the blood-brain barrier. J Gene Med. Aug; 10(8):930-47.

Patent: A PCT patent application has been filed.

TCD Ref: PH01-112-01

Emily Vereker, PhD Technology Transfer Case Manager-Life Sciences Tel: +1 353 1 896-4152
Email: emily.vereker@tcd.ie