Oct 26, 2021

Researchers Prevent Disease Progression in Laboratory Models of Parkinson’s

By Andrea Haman

A team led by University of Toronto researchers has prevented the development of brain changes and movement problems associated with Parkinson's disease in mice. Using a new approach, the research team reduced the levels of a protein that causes Parkinson’s. Their findings make this a promising strategy to explore further, with the goal of one day preventing the disease altogether in humans.

“In our study, we found that reducing the alpha-synuclein protein down to about 50% of its normal levels was sufficient to block it from building up and to prevent the disease," says Anurag Tandon, an associate professor at U of T and a scientist in the Tanz Centre for Research in Neurodegenerative Diseases. He is also the senior author of the study, published last week in Brain Communications.

An “extremely debilitating” disorder, Parkinson’s disease affects mostly people over age 60, says Tandon. By age 80, about 10% to 15% of people will have a form of Parkinson’s or another movement disorder. There is no cure, and existing treatments aim to reduce symptoms. According to Parkinson Canada, more than 100,000 Canadians live with Parkinson’s. Tandon expects the disease will affect more Canadians as baby boomers continue to enter their late-life years.

One cause of the disease appears to be a buildup of alpha-synuclein in the brain. The healthy form of the protein is involved in communication between neurons or nerve cells. In Parkinson’s disease, however, the protein starts to misfold, stick to itself, and form long chains that clump in the brain and eventually damage neurons. Finding ways to reduce the amount of misfolded alpha-synuclein is a focus among Parkinson’s researchers.

For their study, the research team developed and tested an innovative gene-therapy approach. While gene therapy can work in many ways, in this case, the researchers aimed to decrease the activity of the gene that produces alpha-synuclein, which then could reduce the overall amount of the protein to avoid its buildup. Think of it like reducing the number of cars on a highway to reduce the likelihood of traffic blockages, says Tandon.

The team studied two groups of mice that will develop Parkinson’s-like neuron damage and movement impairments: one surgically injected with a therapeutic gene sequence in specific brain regions and one injected with a placebo version as a comparison group. The therapeutic gene sequence reduced the levels of alpha-synuclein and prevented buildups in the targeted regions and throughout the brain. As well, mice with the therapeutic gene sequence maintained their movement abilities, while the placebo group developed an accumulation of alpha-synuclein and subsequent movement problems.

Postdoctoral researcher Sindhu Menon

Postdoctoral researchers Sindhu Menon, in the Tanz Centre, and Rikke H. Kofoed, in the Sunnybrook Research Institute (SRI), conducted the study and are co-first authors on the publication. The team also included several scientists from the Tanz Centre and SRI, and Sanofi Genzyme (part of international biopharmaceutical company Sanofi), which provided the gene sequences. 

The study expands on earlier Parkinson’s research by this team. The previous study investigated a novel method of delivering gene therapy to the brain without surgery, called focused ultrasound. Crossing the protective blood-brain barrier is a major challenge when aiming to get new treatments to the brain.

Postdoctoral researcher Rikke Kofoed

Pioneered by SRI scientists, focused ultrasound uses small beams of sound waves to temporarily increase the permeability of the blood-brain barrier, enabling therapeutic substances to pass from the bloodstream to the brain. This procedure does not require invasive surgery and is being evaluated in humans.

With their team members, Tandon and Isabelle Aubert, a senior scientist at SRI and a professor at U of T, led the study to show that focused ultrasound effectively delivered the gene therapy to four brain regions that are important in the development of Parkinson’s disease.

Next, the team is combining strategies from these two studies in new research that’s underway. They are using focused ultrasound to deliver the therapeutic gene sequence, then assessing the outcomes on alpha-synuclein buildup and movement over a longer period.

Tandon is optimistic about the potential of focused ultrasound and gene therapy to change the course of Parkinson’s disease and other neurodegenerative diseases. Clinical studies to test the safety of focused ultrasound are taking place in people with Parkinson’s disease, Alzheimer’s disease, ALS and brain tumours.

“So it's very exciting,” says Tandon. “We are really at the cusp of a change in how we think about treating diseases. We think that gene therapy can have a major impact on how we can treat neurodegenerative diseases going forward.”

Researchers aimed to prevent buildups of the protein alpha-synuclein (seen in red above) in brain neurons (seen in blue above). Mice that received a therapeutic gene sequence (image on the left) did not accumulate misfolded alpha-synuclein buildups.
Researchers aimed to prevent buildups of the protein alpha-synuclein (seen in red above) in brain neurons (seen in blue above). Mice that received a therapeutic gene sequence (image on the left) did not accumulate misfolded alpha-synuclein buildups.

This study was funded by grants from the Canadian Institutes of Health Research (CIHR) and support from the Canada Research Chairs program. Fellowship and scholarship funding was provided by the Edmond J. Safra Foundation, Canadian Alzheimer Society, Carlsberg Foundation, Ontario Student Assistance Program and CIHR.