Study Rationale: Glucocerebrosidase (GBA) is an enzyme that removes a sugar that is attached to certain fat molecules in the healthy brain. This critical biochemical process begins to malfunction early on in Parkinson’s disease (PD). Many laboratories are developing novel drugs for the treatment of PD that can boost GBA activity, and we are developing probes that can be used to monitor GBA activity in the human brain by positron emission tomography (PET). This approach could help elucidate how dysfunctional GBA promotes neurodegeneration, leading to improved therapeutics and an ability to identify individuals who would benefit from GBA-boosting drugs in clinical trials.
Hypothesis: Our hypothesis is that the promising GBA-imaging probes already discovered by our team can be built upon to develop the next generation of candidates for evaluation in preclinical models of PD, thus enabling us to obtain the data needed to move towards future human studies.
Study Design: To generate PET images that reveal GBA function, subjects are injected with a tiny amount of a radioactive probe that enters into the brain and latches onto GBA. We will prepare next-generation probe candidates with improved performance for testing in preclinical models of PD and, using our well-designed preclinical screening platform, we will identify the best candidates for future human studies. We will also measure the levels of GBA in different brain regions in tissue samples provided by donors with and without PD, which will help us to unravel how GBA dysfunction contributes to neurodegeneration.
Impact on Diagnosis/Treatment of Parkinson’s disease: Tools that provide scientists with images that represent the biochemical function of GBA in the living brain would facilitate assessing the most effective GBA-boosting therapies, monitoring treatment responses, and identify suitable patients for clinical trials. All these outcomes will help investigators develop new and improved drugs for treating PD.
Next Steps for Development: If we succeed in discovering probes that can detect GBA by PET imaging in animals, we will seek additional industrial and academic partners and start the approval process for “first in patient studies.” Further studies will provide validation that the PET method can monitor GBA activity in people with PD.