Although a relatively large number of drugs is available to alleviate the symptoms of Parkinson's disease, there is no therapy available so far that halts or delays the disease progression. This progression usually results in worsening of the symptoms, and eventually renders the Symptoms & Side Effects treatment ineffective. Therefore we are searching for therapies that has an influence on the cause of Parkinson's disease, cell death of a group of specialized nerve cells in the brain that secrete dopamin, an important transmitter of signals in a circuit that regulates movement.
We have recently discovered that a specific protein, granulocyte-colony stimulating factor, is effective in reducing cell death in a pre-clinical model for Parkinson's disease. This protein factor is quite attractive for therapy, because it is known to be well-tolerated in humans. In this project we aim to gather information on this factor, such as an effective dose range, that is eventually needed to progress to clinical trials in patients.
The researchers demonstrated that G-CSF was neuroprotective in a rodent model of PD. In another project, G-CSF was evaluated in an in vivo axotomy model (optic nerve transection model). Here, it was demonstrated that G-CSF neuroprotection is not mediated by its effects on the bone marrow, but predominantly by direct activation of neuronal G-CSF receptors.
Based on these proof-of-principle studies, a pharmacologically improved derivative of G-CSF, called pegfilgrastim, was studied in an extensive pre-clinical evaluation. It turned out that pegfilgrastim also was dose-dependently neuroprotective in the Parkinson’s disease model. Importantly, improved motor function was detected upon pegfilgrastim treatment in the Parkinson’s disease model. A crucial clinical advantage of pegfilgrastim might be its pharmacological properties, with a longer halflife-time and slower cerebrospinal fluid clearance, a finding that could minimize systemic side-effects on the bone marrow but also contribute to patient compliance due to longer injection intervals. As a last step before a clinical feasibility and safety study in Parkinson’s disease patients, respective non-human primate studies are currently being designed.
Results of this project were published in the Journal of Neurochemistry and in Neuroscience.