Objective/Rationale:
Davunetide is an investigational drug with the potential to treat Parkinson disease and is currently in a clinical trial for progressive supranuclear palsy, a rare progressive movement disorder. The goal of this project is to develop an understanding of the optimal dose and length of treatment in an pre-clinical model of PD, known as the alpha-synuclein model. This information will guide future drug development activities for davunetide in PD.
Project Description:
Previously, in a study sponsored by MJFF, the investigators found that treatment with davunetide for two months resulted in an impact on brain pathology as evidenced by a reduction in alpha-synuclein aggregates and a modest improvement in the pre-clinical model’s motor behavior. The current project will expand on these preliminary findings to assess if different doses and/or longer treatment duration will result in a more robust impact on brain pathology and/or improvement in motor function. The alpha-synuclein pre-clinical model was chosen because it progressively develops both the motor function problems and the neuropathology seen in PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The proposed work will be carried out in a pre-clinical model that progressively develops many of the impairments associated with PD including a 40% decrease in dopamine neurotransmitter levels in the brain by 14 months of age. Development of “disease modifying” drugs rather than simply treating the symptoms of the disease requires drug treatment data from an pre-clinical model such as this which recapitulates the progression of PD.
Anticipated Outcome:
The proposed research will help map out the future development of davunetide in PD, including guidance on whether to target early or more advanced stages of disease and selection of the drug dose needed to improve both motor function and modify disease progression by reducing the pathology of PD. Because davunetide is currently in clinical trials, the potential exists to rapidly bridge to a clinical trial in PD.
Final Outcome
Previous pre-clinical research showed davunetide to protect brain cells and improve behavioral deficits after two months of treatment in a pre-clinical model of PD. This project expanded on these initial findings by treating young and aged modelse for a longer period of time (six months) with two doses of davunetide in order to replicate the initial finding and explore the correlation between behavior and the key pathologies responsible. The findings from the current study show davunetide to reduce phosphorylated tau in young pre-clinical models and to have a modest improvement on some of the behavioral outcomes at both ages, however no reduction in alpha-synuclein aggregates was observed at either doses.