Like a GPS, this tracer could identify and monitor the disease progression
by Ali Chou
When we think we are healthy, we may overlook minute symptoms like anxiety or light-headedness. But those can in fact be symptoms of Parkinson’s disease (PD). While Parkinson’s disease is more commonly associated with motor symptoms like tremor, in many cases, and often prior to a diagnosis, patients may experience non-motor symptoms such as mood or cognitive disorders. Some people might think they have mood swings because they are experiencing stress at work, for example. Since some of these issues are not automatically associated with more severe health problems, they can easily be written off, which can get in the way of a timely PD diagnosis.
What if there was a real-time tracking system that could monitor for early onset of aggressive disease, even before severe symptoms appeared? A team of GlycoNet Investigators Drs. Christopher Phenix, Rebecca Davis, Justin Hicks, Darrel Mousseau, and David Palmer are looking to develop just that.
Specifically, the team is working on an injectable tracking device—a positron emission tomography (PET) tracer—that can tell in real-time if a patient is at risk for early onset of PD. PET requires the injection of small amounts of a radioactive tracer to create pictures that measure biochemical activity in the living brain. Due to its unrivaled power to image brain activity, PET is already used in clinics to reveal various neurological disorders.
While the causes for PD are not yet fully understood, one of the earliest changes in the brain is the aggregation of insoluble proteins. This accumulation is heavily correlated with the dysfunction of an enzyme—β-glucocerebrosidase (GCase).
“Patients who have Parkinson’s disease are known to have lower activities of GCase in the brain,” says Phenix. “This enzyme normally functions by recycling cell wastes and metabolites through removal of sugars from fats found in cell membranes. If there is an insufficient amount of GCase, wastes would build up and eventually damage brain cells, resulting in more severe symptoms of Parkinson’s disease earlier on. We are designing a PET tracer to monitor this enzyme’s activity.”
Unlike other PET tracers for PD, which give a snapshot of glucose (sugar) metabolism or dopamine receptor activity in the brain, the version proposed by the GlycoNet researchers would track the activity of GCase. This could give a better indication of early biochemical changes in the brain of PD patients.
“Existing diagnostic PET tracers that monitor dopamine receptors show the areas where brain neurons are dead. At this stage, there is already irreversible damage to those areas of the brain,” explains Phenix. “Whereas tracing GCase would produce a PET image showing the extent of GCase dysfunction. Recent evidence suggests that this phenomenon occurs at a much earlier stage in Parkinson’s disease.”
In medicine, earlier is always better. Early diagnoses enable patients to receive appropriate care and treatment sooner.
However, designing a radioactive tracer that can image GCase is no easy task. It involves several complex steps. First, investigators need to design, synthesize, and optimize radio-labeled molecules that bind to GCase—usually this step involves multiple iterations of improvement to tease out a set of best candidate molecules. Second, the team conducts exhaustive testing in neuronal cells and animal models before the molecules can be put through clinical trials in humans. Prior to moving into a full scale clinical trial, in-patient studies are necessary to confirm that the tracer can image GCase in humans. The team needs to be made up of experts from different fields in order for the process to move along seamlessly.
“It is much more efficient to have various experts working within a collaborative team throughout the project,” says Phenix. “Dr. Rebecca Davis (University of Manitoba), for example, uses computers to identify lead compounds that will bind to GCase; she looks at the enzyme’s structure in 3D and helps us optimize the affinity of the compound to our target. Based on her advice, we then prepare the compounds she has identified and test them in the lab.”
Phenix is also collaborating with two other Investigators from University of Saskatchewan and one from the Lawson Health Research Institute in Ontario. Dr. Palmer (University of Saskatchewan) is helping the team synthesize and identify new compounds that efficiently target GCase. Dr. Mousseau (University of Saskatchewan) provides expertise in neurobiology to evaluate the radiotracers in cells and animals, while Dr. Hicks (Lawson Health Research Institute) leverages his knowledge of radiotracers in the brain to inform the team’s next steps.
At this stage, the multidisciplinary team has developed synthetic routes to efficiently prepare a variety of radio-labeled derivatives and have identified promising compounds based on experiments using neuronal cells. The group is moving towards preclinical studies to ensure that the radioactive compounds can trace GCase in living animals properly. “Selectivity,” or the act of binding only to the target enzyme, will be validated in living animals during this phase of the research process.
“Selectivity of the tracer is absolutely critical,” say Phenix, “there are over ten thousand other proteins in the body, and there are three other enzymes that are very similar to GCase. We need to make sure our tracer only binds to GCase, so that the PET image would show the accurate trace.”
In addition to being used as a diagnostic aid for PD, the PET tracer could potentially facilitate the development of new PD therapeutics. “There are several companies developing therapeutics that aim to increase GCase activity. Our tracer could help guide their development—by tracing GCase, we can tell which drug candidates are most effective in increasing the enzyme’s activity,” says Phenix.
If Phenix and his collaborators are successful in developing a PET tracer, the team believes this can benefit neurologists, researchers, and patients by using the tracer as a tool to understand the biology of PD and potentially as a diagnostic aid.
“There are certainly examples where it can be difficult to distinguish Parkinson’s disease from related disease, such as dementia with Lewy bodies (aggregation of insoluble proteins). We hope that our tracer could become a diagnostic aid to confirm and identify the disease earlier, improving patient’s quality of life,” says Phenix.