Study Rationale: Peptide-based drugs are attractive candidates for treating the cognitive decline associated with Parkinson’s disease (PD) because they demonstrate a robust safety profile and an ability to counteract degenerative brain changes in PD. By adding sugar molecules to such peptide drugs, we have improved their stability and their ability to enter the brain from the blood stream. Our lead drug, the glycopeptide PNA5, protects against cognitive decline in preclinical models of another form of dementia, vascular dementia. We also determined that a two-month treatment with PNA5 reduces cognitive symptoms in a PD mouse model by dampening neuroinflammation.
Hypothesis: We hypothesize that PNA5 will improve symptoms and pathology in a well-characterized preclinical model of PD (mice engineered to overproduce human alpha-synuclein) via its effect on the Renin Angiotensin System in the brain, a system that is associated with cognition enhancement and neuroprotection.
Study Design: We will extend our assessment of the therapeutic effects of PNA5 in the PD mouse model by comparing two different doses and their ability to enhance cognition. After administering drug treatment, we will conduct a battery of behavioral tests assessing cognition as well as motor function, followed by other cellular and molecular analyses in multiple brain regions to understand how PNA5 alters PD-relevant pathology, especially neuroinflammation. Using gene-expression profiling, we will study the biological mechanisms involved in PNA5’s effects on cognitive function. We will also evaluate several potential clinically relevant biomarkers to track the effects of PNA5.
Impact on Diagnosis/Treatment of Parkinson’s disease: These studies will demonstrate, for the first time, the translational utility of the glycopeptide PNA5 for treating cognitive decline in PD, reveal the mechanisms through which PNA5 acts and identify biomarkers that can be used to monitor PNA5’s efficacy.
Next Steps for Development: Data will be generated in a well-characterized preclinical PD model. With the first-in-human trials for PNA5 planned for 2024, the results will set the stage for rapid future clinical trials to test PNA5 treatment in individuals with PD-associated dementia.