Crossing the blood-brain barrier: key to new treatments for Alzheimer's, other neuro diseases

- Ottawa, Ontario

In collaboration with researchers at one of the world's leading biotechnology companies, neuroscientists at the National Research Council of Canada (NRC) are working to find pathways to deliver therapeutics through the blood-brain barrier—what could be a major step in the development of new treatments for neurological diseases such as Alzheimer's, multiple sclerosis (MS), Parkinson's, amyotrophic lateral sclerosis (ALS) and even brain cancer.

Barrier protects the brain, but…

As NRC Senior Research Officer Dr. Arsalan Haqqani explains, the cells that make up the blood-brain barrier perform a unique and crucial function: they keep toxins and pathogens in the bloodstream from entering and causing damage in the brain, while allowing vital nutrients to get in.

"Unfortunately, in doing their job, these cells also prevent a majority of therapeutics designed to treat neurological disorders from getting in," says Dr. Haqqani. "Because of this, to ensure enough of a medication reaches the brain, very large doses must be administered. This leads to unwanted and potentially dangerous side effects—one of the main reasons many promising treatments for these neurological diseases have failed."

Finding a way in

Dr. Haqqani's team at the NRC's Human Health Therapeutics (HHT) Research Centre, in collaboration with the NRC's Digital Technologies Research Centre, has developed a promising foundation for a workaround.

Using genomics and other "omics" technologies, as well as bioinformatics to analyse and manage the data they generate, the NRC team has developed what they call the Brain Beyond Barriers CARTA—a detailed molecular map of genes and proteins expressed in brain cells, including cells from the blood-brain barrier.

The information contained in the BBB CARTA and the techniques involved in creating it can be used to identify new pathways and targets in the brain to inform the development and delivery of drugs and other therapeutics to the brain—features that have attracted the attention of biotechnology company, Biogen.

Genomics investment enables promising partnership

Based in Cambridge, Massachusetts, Biogen focuses on developing treatments for neurological diseases.

With funding support from the Government of Canada's Genomics Research and Development Initiative (GRDI), the HHT team is working with scientists at Biogen, using the BBB CARTA to analyse the surface of brain endothelial cells, cells that make up the blood-brain barrier, and employing algorithms to identify targets most likely to facilitate the transport of medicines through the barrier.

"Once we have identified target receptors, we engineer antibodies designed to bind to these receptors taking advantage of the same pathway the cells use to deliver nutrients through the barrier," says Dr. Haqqani. "Antibody engineers at Biogen and HHT can attach a therapeutic to the antibodies, which can sneak the medicine through the barrier and into the brain—the BBB-crossing antibodies are like a Trojan horse."

Valued collaborator

At Biogen's global head office in Massachusetts, Head of Biologics Drug Discovery Dr. Paul Weinreb says, as pioneers in neuroscience, the team at Biogen is excited to be working with the NRC to improve the delivery of medicines to the brain.

"The close partnership between Biogen and the NRC has provided important insights into targets and pathways that may lead to higher levels of transport of antibodies and other therapeutic modalities across the blood-brain barrier," says Dr. Weinreb. "Ultimately, this has the potential to lead to improved next-generation treatments in areas like Alzheimer's or Parkinson's."

BBB CARTA influence continues to expand

The BBB CARTA is updated on an ongoing basis with new and emerging data generated from studies performed at HHT and other research organizations. In addition to the way CARTA is being used in the NRC-Biogen collaboration, it has numerous other uses, including developing methods to identify potential therapies most likely to translate successfully from animal models to humans.

"We have taken advantage of cutting edge "omics" technologies such as next generation sequencing, proteomics and bioinformatics to create a unique molecular map of the blood-brain barrier," says Dr. Danica Stanimirovic, Director of the Translational Bioscience Department at HHT. "This has led to both better understanding of its function and important breakthroughs in the development of therapies for brain diseases."

The NRC has made the BBB CARTA available for use by other researchers, and it is being used to inform the work of a number of partnerships between the NRC and researchers in both academia and industry aimed at developing and advancing novel therapies for brain diseases.