Promising Outcomes of Original Grant:
We have discovered that a specific protein, granulocyte-colony stimulating factor (G-CSF), is effective in reducing nerve cell death and thereby disease progression in a pre-clinical model for Parkinson's disease (PD). This protein factor is quite attractive for therapy, because it is known to be well-tolerated in humans. In a detailed preclinical evaluation, we could show that a chemically modified version of G-CSF, called pegfilgrastim, is at least as effective as conventional G-CSF, has the advantage that it needs to be injected less frequently and will most likely be associated with fewer side effects in a clinical setting. Moreover, we gathered further pharmacological information on this factor in the mouse PD model, such as an effective dose range and cerebrospinal fluid pegfilgrastim levels, which is the basis for the subsequent studies in pre-clinical models.
Objectives for Supplemental Investigation:
Based on the information gathered in the original project, we will pursue the development of this new treatment option in a PD model. This work is aimed to confirm the efficacy of pegfilgrastim, to gain safety experience with extended periods of pegfilgrastim application and to obtain important further pre-clinical information, e.g. regarding levels of pegfilgrastim in the blood and the cerebrospinal fluid. These data will be necessary for the planning of a clinical study. The project thus represents the last step before a clinical feasibility and safety study in Parkinson’s disease patients could be performed.
Importance of This Research for the Development of a New PD Therapy:
Medical treatment to alleviate the symptoms of Parkinson's disease is available, but progression of the underlying disease eventually renders the Symptoms & Side Effects treatment ineffective after years. There is no therapy so far that halts or delays the disease progression itself. Pegfilgrastim might turn out to be the first treatment that does not only temporarily ameliorate disease symptoms, but halts or delays progressive degeneration of a group of specialized nerve cells in the brain, which is the cause for Parkinson’s disease progression.
The aim of this study was to evaluate the pre-clinical protective effects of pegfilgrastim, a modified version of the cytokine granulocyte-colony stimulating factor (G-CSF) in a model for PD. G-CSF has been shown to have neuroprotective, anti-apoptotic and anti-inflammatory effects in various models in vivo. Pegfilgrastim has a long half-life that makes it suitable for chronic treatment of neurodegenerative disease. Our pre-clinical study was designed to obtain information on pharmacokinetics, potential side effects and neuroprotection. We demonstrated that pegfilgrastim crosses the blood-brain barrier, and observed long-lasting high pegfilgrastim levels in the serum. Routine clinical chemistry did not reveal alterations in liver or kidney function or disturbances in serum electrolytes during pegfilgrastim treatment for nine weeks. Most importantly, pegfilgrastim treatment prevented motor deficits induced by the neurotoxin MPTP, although dopaminergic cell numbers in the SN remained unchanged. We are currently investigating the possibility that degeneration of striatal dopaminergic nerve terminals is responsible both for MPTP-induced motor deficits and respective protection by pegfilgrastim. Taken together, a relatively rapid transfer of this treatment to the Parkinson’s disease clinic is desirable and might be possible since a safety profile exists for the short-term use of pegfilgrastim in other human disease conditions.