By Ashleigh Mattern for SHRF
Chris Phenix says a bit of luck is required whenever researchers are developing new chemical entities or drug candidates.
“You’re really trying to outsmart biology,” said Phenix, assistant professor in the chemistry department at the University of Saskatchewan. “We’re trying to design compounds that can image one enzyme out of 10,000 proteins. … Nature will humble you real quick.”
Phenix and his team are working to develop radiotracers to detect Parkinson’s Disease, a chronic degenerative brain disorder that affects more than 100,000 Canadians. The radiotracers selectively attach to an enzyme known as GCase (glucocerebrosidase), which drops in the brains of Parkinson’s patients.
Currently, there are no radiotracers available to image GCase in patients, and the techniques could be used both to diagnose Parkinson’s, particularly in people with aggressive cases, and to help develop new drugs for the disease.
This groundbreaking work has garnered $150,000 (USD) in funding from the extremely competitive Michael J. Fox Foundation, drawn interest from multinational drug companies, and attracted collaborators and clinicians from across the country.
Phenix credits much of his success with the funding his team received through the Saskatchewan Health Research Foundation Establishment Grant. He says that grant allowed his team to take early chemical tools that attach to the GCase enzyme in a test tube and make improved versions that were effective in more complicated biology experiments.
Now, their work has shifted to try to convert those compounds into positron emission tomography (PET) radiotracers using the new cyclotron facility on campus to detect the enzyme in patients.
“We’re starting to translate from neurons in a dish to actual patient brain samples; we’re moving from cell models and animal models to human samples,” he said.
Potential for new treatments
There’s a lot of interest in developing new types of drugs that target GCase to treat aggressive Parkinson’s disease. His team is in negotiations with multinational drug companies that are interested in developing drugs using the imaging technology.
“Since the activity of GCase drops in Parkinson’s, companies are trying to find ways to boost the activity, so restore normal functioning of that enzyme, which they hypothesize would lead to a slower progression of the disease.”
A major challenge with developing drugs is being able to prove that the drug candidate is interacting with the protein that you think it’s interacting with, he said. In the past, the tools that researchers have used to study enzymes like GCase have not been selective. This means that the results of an experiment are difficult to interpret.
“There’s a lot to be learned about what is actually happening inside neurons once you have chemical tools that are selective to the target,” Phenix said.
Addressing real-world issues
Many collaborations have resulted from his team’s work as well. Other project members include Aarnoud Van der Spoel, assistant professor in biochemistry and molecular biology at Dalhousie University; neurologists Ali and Alex Rajput, who have contributed greatly to Parkinson’s studies at USask; Darrell Mousseau, a neurobiologist at USask, and clinicians in Toronto and Halifax.
Phenix says it’s difficult for basic researchers like chemists to catch the attention of clinical specialists.
“They’re very busy people, so unless you have something really attractive that you can help them with, and they can help you make some significant advancements in the field, you’re not going to be able to work with them,” Phenix said.
This research could help the scientific and medical communities better understand the molecular mechanism of disease progression, so the collaboration also gives clinicians the opportunity to deepen their understanding of the disease.
Having clinicians on board with the research also benefits Phenix’s team because it helps them ensure they’re addressing real-world important issues.
“You really find out what [the clinicians] are struggling with,” he said. “It helps you hone in your efforts to solve really important problems that the health experts are needing solutions for.”
‘The wild west’
Phenix, who grew up in the southeast part of the province, came back to Saskatchewan from Ontario in 2016, and he said the SHRF funding helped him, and his team hit the ground running when he started working at USask.
That head start ended up being critical to his team’s success, allowing them to be competitive in this research field. There is another lab in Canada and one in the Netherlands that is studying a similar line of research, and the SHRF funding allowed Phenix’s lab to stay one step ahead.
Now, this research, supported by the cyclotron facility, is also leading to other lines of investigation. They’re also using these nuclear medicine techniques to study plants. As it turns out, there are some crop plants that have the same enzymes that they’ve been studying in relation to Parkinson’s.
That research is in its early stages, but the same tools they’re developing to study Parkinson’s may be able to be used in plant research to develop more drought or disease resistant varieties, for example.
“Being a chemist and making new compounds is exciting as it's sort of like the wild west, the frontier, the pioneers.”
New USask radiotracers could be key for new treatments and early detection for Parkinson’s
The Development of Novel Probes for Imaging Glucocerebrosidase Activity in Parkinson’s Disease