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The blood-brain barrier protects our brain from potential threats such as bacteria. But it also blocks potential treatments for brain tumours and other diseases. Now, a molecular Trojan horse could change that.
It’s our brain’s natural guardian — a virtually impenetrable wall that protects the brain from harm. Called the blood-brain barrier, this high-security fence consists of densely packed endothelial cells (which line the surface of blood vessels) and biochemical pumps that block foreign substances from entering brain tissues from the capillaries that feed the brain.
“Our brains need a strictly regulated microenvironment for neurons to function,” says Dr. Danica Stanimirovic, a neurobiologist at NRC. “In order to maintain that environment, the blood vessels in our brain are tightly regulated and tightly linked to prevent virtually everything from entering the brain — more than 95 percent of all molecules in the bloodstream cannot cross the blood-brain barrier.”
The blood-brain barrier only allows in certain molecules that the brain needs, such as essential nutrients and insulin. It excludes just about anything that could pose a risk to the central nervous system, including foreign molecules and bacteria cells. “But it also blocks potential treatments for diseases such as brain tumours, multiple sclerosis and Alzheimer’s disease,” says Dr. Stanimirovic.
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Neurological diseases account for more than 35 percent of the total burden of disease in developed economies. “The current cost of treating neurological disease is enormous, and the projected cost is going to skyrocket because of our aging population,” says Dr. Stanimirovic.
Dr. Stanimirovic is leading an NRC team that has engineered a new tool to sneak drugs past the blood-brain barrier. Their research could play a key role in unblocking a growing pipeline of potentially useful therapies developed by drug companies. Most of these pipeline drugs are large molecules such as antibodies and vaccines — none of which will spontaneously go into the brain, she stresses. Although methods exist for administering drugs into the brain, such as direct injections, they are highly invasive and inappropriate for patients who require daily medication.
The NRC approach involves a family of antibodies discovered in “camelids” (which include llamas and camels) that have a “single-domain” for recognizing molecules and are ten times smaller than the antibodies found in humans. These antibodies are engineered both to carry a drug, and to recognize and “fit” into a specific receptor molecule located on the surface of blood-brain barrier cells.
When the antibody-drug payload contacts this receptor, the whole antibody-drug-receptor complex is engulfed by the cell — like a Trojan horse — and then transported across and out the other side. “So far, we’ve isolated several promising antibodies, of which one in particular is an effective carrier of drugs into the brain,” says Dr. Stanimirovic.
“This is a platform technology, which means that one company could use it to deliver their favourite drug and another company to deliver their favourite peptide into the brain,” she adds. “NRC is currently working with partners on potential drugs for different diseases, including Alzheimer’s.”
The NRC team is also exploring methods of increasing the payload their Trojan horse can carry across the blood-brain barrier. “We’re developing a nanoparticle that can be stuffed with drug molecules or imaging agents and attached to single-domain antibodies,” explains Dr. Abedelnasser Abulrob, the NRC scientist who leads this initiative.
In 1993, scientists discovered that unlike other mammals, the “camelid” family (which includes llamas and camels) produces two types of antibodies: conventional Y-shaped antibodies — found in all mammals — consisting of four polypeptide chains; as well as antibodies that contain only two polypeptide chains. Within the two-chain antibodies, the part that recognizes and clings to foreign molecules (or “antigens”) during an immune attack is called a single-domain antibody.
Single-domain antibodies have a high affinity for their target antigens and are highly stable in different pH, temperature and other conditions. These proteins can also be mass-produced easily in E. coli and other microorganisms, such as yeast, making them cost-effective therapeutics.
“About a decade ago, we developed a library of single-domain antibodies — containing almost one billion clones — to take advantage of their properties for targeted drug research and development,” says Dr. Jamshid Tanha, a molecular biologist in NRC’s Antibody Engineering Group. “We have successfully exploited the library as a source of single-domain antibodies against several therapeutic targets and the brain’s Trojan horse receptor.”