For patients battling neurodegenerative diseases like ALS, Parkinson's, Alzheimer's and other dementias, delivering disease-fighting antibody drugs directly to the brain has proven to be a difficult task. Our bodies set up tight walls to prevent infections from spreading to the brain, where they often become fatal. Unfortunately, this protective feature also prevents us from getting drugs into the brain. Approximately 1 in 10,000 antibodies injected into patients actually make it to the brain, with these cellular fighters trapped in the blood rather than escaping through cracks in the blood vessels into the brain.
Now, researchers have mapped out a new transit process to enable drugs to reach the brain which uses extracellular vesicles – which are like tiny bubbles naturally produced by cells in our bodies: Researchers at the University of Ottawa, showed that extracellular vesicles find a way to squeeze through blood vessels into the brain, allowing them to deliver drugs there. As a next step, they wanted to find ways to improve the ability of antibodies in the brain to eliminate the pathological proteins that cause neurodegenerative diseases.
"Normal antibodies can attach themselves to the disease-causing proteins in these diseases, but they can't eliminate them and so aren't as potent as they could be," explains Dr. Derrick Gibbings , a Professor in the Department of Cellular and Molecular Medicine at the University of Ottawa (uOttawa).
Taking out the trash
Autophagy is the body's natural recycling plant, collecting waste from the cell and breaking it up into the small pieces that can be re-used to build other things useful to cells. This allows the body to break them down and reuse things. Dr. Gibbings' team engineered antibodies which attach themselves to disease-causing proteins with a baggage tag that directs these disease-causing proteins into the autophagy garbage disposal system to eliminate whatever the antibodies bind.
"It's a natural cleaning out process that is normally activated when your cells are stressed or deprived of nutrients. In cells and mouse models we showed that using autophagy improved elimination of the proteins which cause Alzheimer's, Dementia and Amyotrophic Lateral Sclerosis greatly and mice showed improvements in their symptoms of disease" says Gibbings. This research, led by a research associate in Dr. Gibbings lab, Huishan Guo are published in the journal Nature Biomedical Engineering .
Future promise
While this discovery is cause for optimism, Dr. Gibbings reminds us this is a first step. Treating mice is one step, but an important one, on the road toward clinical trials and showing benefits in patients.
"There is a lot of enthusiasm for antibodies like these in industry, with many of the major pharma and biotech companies having invested billions of dollars in this space," says Dr. Gibbings, a member of the Eric Poulin Centre for Neuromuscular Disease . "Many of these antibodies have been tried in patients in clinical trials but have shown minimal benefits to patients so far. We hope our new strategy to get these antibodies into the brain and eliminate their targets may be a key to making these drugs work for patients."
