New Gene therapy approaches for treatment of Parkinson’s disease
Mathias Bähr
Department of Neurology, University of Göttingen Medical School, Robert-Koch-Str.40, 37075 Göttingen, Germany
Abstract:
The majority of human neurodegenerative diseases develop with increasing age and show a multifaceted pathology with signs of synaptic dysfunction, oxidative stress and axonal degeneration preceding neuronal cell loss. The latter often displays features of programmed cell death. The pro-apoptotic signals that have been described so far seem to initiate breakdown of mitochondrial membrane potential, followed by the release of proapoptotic factors from the inner mitochondrial membrane and subsequent caspase activation. Thus, to develop a versatile neuroprotective therapy for several different disorders that makes the affected neurons more resistant to stress stimuli one needs to focus on the maintenance of mitochondrial integrity e.g. by overexpression of antiapoptotic members of the Bcl-2 family of proteins, neurotrophic factors or other upstream regulators of mitochondrial morphology and membrane integrity. This approach, in contrast to inhibition of downstream events after AIF or cytochrome C release, apoptosome formation and Caspase activation may prove much more effective in protecting affected cells from dysfunction and subsequent cell death. Glial cell line-derived neurotrophic factor (GDNF) is a promising candidate in the long-term treatment of Parkinson’s disease, but its route of application is complicated and may explain the variable outcome in recent clinical trials. To elucidate effective and long-lasting neuroprotective strategies, we analysed a combination of mitochondrial protection and neurotrophic support in two well-defined animal models of neurodegeneration, traumatic lesion of the optic nerve and 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway. Neuroprotection by BclXL, Glial cell line-derived neurotrophic factor (GDNF) or BclXL combined GDNF co-expression were studied using modified AAV for gene transfer. We could show that BclXL expression is more important for neuronal survival in the early phase after lesions, whereas GDNF-mediated neuroprotection becomes more prominent in the advanced state of neurodegeneration.
To further develop this approach, we have successfully applied and been rewarded with a new grant in the 7th EU-Framework programme (FP7) where we have developed more sophisticated AAV and Lentivirus based Gene Therapy techniques in a consortium of the major academic centres in Europe together with a Biotech company. To that end, we have recently achieved long-lasting, cell-type specific, regulatable vector systems for CNS gene therapy with low or no immunogenicity. The presentation will include the new findings that result from this cooperation and from the scientific interactions within the research focus ‘Aggregation Disorders’ within the Cluster of Excellence at German Elite University Göttingen.
