By Sarath Peiris for the University of Saskatchewan
An estimated 55,000 Canadians over age 18 have been diagnosed with Parkinson’s disease, characterized by symptoms such as tremors, muscle rigidity and unstable balance.
A diagnosis of the neurodegenerative disease can be tricky, and only fully confirmed by examining a patient’s brain after death. Its symptoms usually emerge only when a significant number of dopamine-producing neurons in the brain are dead.
But now a multidisciplinary team from three provinces, led by University of Saskatchewan (U of S) and SHRF-funded researcher Chris Phenix, is studying a way to identify Parkinson’s sooner.
Techniques that specifically detect Parkinson’s earlier mean interventions can begin sooner, especially for young people, and potentially mitigate the loss of neurons.
Using fluorine-18 provided by the Saskatchewan Centre for Cyclotron Sciences at the U of S, Phenix’s team is studying an enzyme in the brain whose levels have been found to drop off rapidly and early in Parkinson’s patients. The research could lead to the development of new drugs to treat the disease in its early stages.
That enzyme, known as glucocerebrosidase (GCase), has recently attracted considerable attention from the Parkinson’s research community and been identified as a high priority therapeutic target and diagnostic biomarker for the disease.
“The biggest value of this project comes from the development of a clinically relevant research tool to figure out if GCase is playing a critical role in Parkinson’s and, if it is, to help researchers develop better medicines and get those drugs into the clinic to improve therapy,” Phenix said.
His team wants to build on promising preliminary results obtained from in vitro tests on living cells.
With promising radiotracer ligands (molecules that produce a signal by binding to a target protein) they have discovered, Phenix and his colleagues will use positron emission tomography (PET) to peer into the biochemistry of the living brain. These ligands selectively attach to GCase enzymes in the brain.
Read more about Phenix’s SHRF-funded Establishment grant project that provided the preliminary steps towards the development of a PET method as a research tool to investigate the role of glucocerebrosidase in Parkinson's disease.
“When the technology matures, we hope to use these radiotracers to non-invasively and safely study the activity of GCase in the living brain at the PET centre at Royal University Hospital,” he said.
Phenix, who describes himself as a chemist, radiochemist, enzymologist and “somewhat of a jack of all trades,” has been awarded $392,000 by the national research network, GlycoNet, and the Saskatchewan Health Research Foundation (SHRF) toward the two-year project. Two graduate students and two post-doctoral fellows (part-time) will participate in the project.
The cyclotron facility, operated at the U of S by the Sylvia Fedoruk Canadian Centre for Nuclear Innovation, is contributing fluorine-18 to the project. The facility includes labs for safely handling radiochemicals, where Phenix’s team will be developing and evaluating the radiotracers.
The other major partner providing crucial in-kind support is Lysosomal Therapeutics Inc. of Boston, which specializes in therapies for neurodegenerative diseases.
Several pharmaceutical companies have drugs that activate GCase, Phenix said. Only patients with low levels of the enzyme would benefit from these targeted medicines.
That’s why PET is emerging as a critical tool for academic and pharmaceutical researchers. The research can help them identify the best drug sooner, and choose for clinical trials only those patients most likely to benefit from the drug.
Phenix’s team includes U of S professors David Palmer in chemistry, who is helping with enzymology and developing new compounds, and Darrell Mousseau in psychiatry, who holds a research chair in Alzheimer’s and related dementias and will provide neurobiology expertise.
Also on the team are University of Manitoba chemistry professor Rebecca Davis, who will design computational studies to help identify suitable ligands and how they interact with GCase, and Justin Hicks, a radiochemist at the Lawson Health Research Institute in London, Ontario, who is contributing to brain imaging.
“Our team will prepare and identify the best compounds that get into the brain, crossing the protective blood-brain barrier that says, ‘You are not supposed to be in here,’ and pumps out certain drugs or radiopharmaceuticals,” Phenix said.
Identifying a suitable PET tracer is anticipated within two years. Testing on human subjects will then happen quickly, Phenix said, because radiotracers only are given at safe microdoses, and the team will have done many of the necessary preclinical studies.
But he acknowledges there will be challenges: “If this was easy, it would have been done already.”
Sarath Peiris is Assistant Director of Research Profile and Impact at the University of Saskatchewan.