With funding support from the Government of Canada's Genomics Research and Development Initiative (GRDI), a team led by Health Canada Research Scientist Dr. Jessie R. Lavoie is helping to ensure Canadian researchers and regulators have the tools they need to assess the therapeutic potential of extracellular vesicles.
More than a curiosity
Extracellular vesicles (EVs) are nanoparticles naturally secreted by all cells. When first discovered, it was believed that EVs were just a cell's way of ridding itself of unnecessary proteins and other materials it didn't need. However, as research into the possible medical applications of human mesenchymal stem/stromal cells (hMSCs) has progressed, scientists have discovered that these EVs act a lot like the hMSCs they came from.
Similar benefits, fewer risks
Hollow-fiber bioreactor set up and ready for EV production in Dr. Lavoie's lab in Health Canada's Centre for Biologics Evaluation (photo: J.R. Lavoie's lab)
From her lab at Health Canada's Centre for Biologics Evaluation (CBE) in Ottawa, Dr. Lavoie says there is justifiable excitement surrounding EVs.
"EVs secreted by hMSCs behave very much like hMSCs themselves, showing a similar potential to regenerate damaged tissue and modulate the immune system, meaning they could be administered in the body without eliciting an immune rejection," says Dr. Lavoie. "And they have an additional benefit: EVs are not living cells—they can't reproduce, so there's no danger they will mutate and become cancerous."
Telling the good guys from the bad guys
Still, EVs are not completely risk-free. At the moment, for example, EVs being considered for therapeutic use are identified and isolated based primarily on their physical properties, including their size.
"EVs are nanoparticles which are a hundred times smaller than the cell that secreted them," explains Dr. Lavoie. "That makes them about the same size as many viruses, which are isolated using a similar process. You certainly don't want any confusion there. There's also the need to discriminate between EVs from normal/healthy hMSCs and those released by abnormal hMSCs that could promote disease."
Applying advanced genomics and other technologies, Dr. Lavoie and her team have identified a protein that appears consistently in high abundance on the surface of EVs secreted by normal/healthy hMSCs—providing an accurate way to distinguish EVs from other nanoparticles as well as to enrich them for therapeutic use. In collaboration with the Bureau of Food Surveillance and Science Integration (BFSSI) Bioinformatics Division in the Food Directorate (FD) and the Mass Spectrometry laboratory from CBE, Dr. Lavoie's team continues to search for other proteins unique to the surface of these EVs in order to develop a panel of biomarkers that would bring additional confidence to their identification and use.
More EVs needed. Lots more.
As a second step in the project, Dr. Lavoie and her team have been working to address another key issue: how to produce the massive quantities of high quality EVs needed for research and potential treatments.
"For therapeutic use, a single dose requires billions of EVs, but scaling up production of almost anything can lead to quality issues," says Dr. Lavoie. "We needed a way to produce large quantities of consistently high quality EVs and do it at an affordable price."
Dr. Lavoie and her team discovered that, by filling up a relatively common device, a hollow-fiber bioreactor, with hMSCs, they could harvest large quantities of EVs on a continuing basis. The even larger quantities needed for commercial use could be produced simply by bringing more bioreactors on-line (imagine a warehouse filled with rows of bioreactors).
Opening the door to more research
Along with its relative simplicity, the big advantage of this method is the cost. "You can set up and start producing EVs for about $5,000, compared to more than $200,000 for other bioreactor-based production methods," says Dr. Lavoie. "That affordability means more researchers can enter the field and more researchers means more knowledge and a faster pace of development for new treatments."
The EV production method developed through this GRDI-funded research is already being used to produce EVs for two studies being conducted in collaboration with scientists at the University of Ottawa—one is exploring the potential of EVs to regenerate brain tissue damaged by stroke, and the second as a potential treatment for highly aggressive triple negative breast cancer for which there are limited treatment options.
Putting Canada on the frontier
The EV-breast cancer study is co-led by Dr. Lisheng Wang, a professor in the University of Ottawa's Department of Biochemistry, Microbiology, and Immunology, who says Dr. Lavoie and her team are making an important contribution. "There is no question of the potential of EVs to be the basis of new treatments for a range of indications," says Dr. Wang, "That is why EV research is growing so quickly and the work Dr. Lavoie is leading is really on the frontier of that research."
The results of Dr. Lavoie's research were published in early 2021, and have already been cited by a number of researchers around the world. In addition, Dr. Lavoie is now passing on her knowledge to a new generation of researchers as an adjunct professor at the University of Ottawa.