Long-term rAAV-mediated gene transfer of GDNF in the rat Parkinson's model: Intrastriatal but not intranigral transduction promotes functional regeneration in the lesioned nigrostriatal system

Wallenberg Neuroscience Center, Department of Physiological Sciences, Division of Neurobiology, Lund University, 223 62 Lund, Sweden.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2000; 20(12):4686-700.
Source: PubMed


Previous studies have used recombinant adeno-associated viral (rAAV) vectors to deliver glial cell line-derived neurotrophic factor (GDNF) in the substantia nigra to protect the nigral dopamine (DA) neurons from 6-hydroxydopamine-induced damage. However, no regeneration or functional recovery was observed in these experiments. Here, we have used an rAAV-GDNF vector to express GDNF long-term (6 months) in either the nigral DA neurons themselves, in the striatal target cells, or in both of these structures. The results demonstrate that both nigral and striatal transduction provide significant protection of nigral DA neurons against the toxin-induced degeneration. However, only the rats receiving rAAV-GDNF in the striatum displayed behavioral recovery, accompanied by significant reinnervation of the lesioned striatum, which developed gradually over the first 4-5 months after the lesion. GDNF transgene expression was maintained at high levels throughout this period. These results provide evidence that rAAV is a highly efficient vector system for long-term expression of therapeutic proteins in the nigrostriatal system.

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    • "The neuroprotective properties of GDNF mentioned above have generated a great deal of interest in the development of GDNF-based gene therapy strategies to treat PD. In rats and non-human primates, administration in the striatum or in the SN of adenoviral [55] [56] [57], herpes simplex virus (HSV)-derived [58], lentiviral (LV) [59] [60] [61] or rAAV vectors [62] [63] [64] for GDNF has been shown to protect nigral DA neurons from the toxic action of DA toxins. In this context, rAAV and LV vectors are emerging as the most promising tools for long-term high-level transgene expression in the brain. "
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    • "The CDNF immunoreactivity in some solitary cells in the ipsilateral lateral GP would also indicate anterograde transport (of protein or viral vector) via the indirect GABAergic pathway. GDNF is known to be transported in both a retrograde (through DAergic projections) and anterograde (through both direct and indirect GABAergic projections) fashion to the SN after intrastriatal injection of either the protein (Tomac et al. 1995b; Ai et al. 2003) or viral vectors encoding GDNF (Kirik et al. 2000; Kordower et al. 2000; Eslamboli et al. 2003; Johnston et al. 2009; Ciesielska et al. 2011). Also in our hands, AAV-GDNF-treated rat brain showed clear GDNF staining in the injected area (striatum), lateral GP, SNpc, and SNpr. "
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