Challenge: The blood-brain barrier (BBB) is a tightly woven layer of vascular cells in the brain that prevents harmful molecules from the circulation, viruses and toxins, from entering the brain. To allow entry of nutrients into the brain, the BBB employs molecular transporters that shuttle nutrients back and forth between blood and the brain across these barrier cells. Unfortunately, the same barrier that protects the brain is also an obstacle for brain delivery of therapeutics to treat brain diseases. Special strategies have to be developed to ‘sneak’ therapeutics passed the BBB. One such strategy is to link therapeutics to molecules that bind natural barrier transporters; potential therapeutics thus ‘hitch a ride’ across the barrier using a natural molecular shuttle as a Trojan horse.
Solution: In the proposed project, a Canadian company biOasis Technologies Inc, National Research Council of Canada and Université de Sherbrooke will develop very small human antibodies (10-fold smaller than regular antibodies) as molecular Trojan horses to enable delivery of therapeutics across the BBB. The team will screen thousands of antibodies to identify those that can efficiently cross the blood-brain barrier and that also can be linked to many different therapeutic molecules. The team will then develop ‘fusion’ molecules consisting of the BBB-crossing mini-antibody and selected therapeutics. The efficacy of these ‘fusion’ molecules in treating brain diseases such as brain tumors will be tested in animals. New non-invasive imaging methods by PET scan will be used to monitor brain penetration of BBB-crossing antibodies.
Impact: If proven effective, these novel BBB ‘carriers’ will be transferred to pharmaceutical companies who will link them to many more ‘old’ and new therapeutics to develop improved treatments for devastating brain disorders.