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The Journal of Neuroscience, August 1, 2000, 20(15):5587-5593

Complete and Long-Term Rescue of Lesioned Adult Motoneurons by Lentiviral-Mediated Expression of Glial Cell Line-Derived Neurotrophic Factor in the Facial Nucleus

Andreas F. Hottinger, Mimoun Azzouz, Nicole Déglon, Patrick Aebischer, and Anne D. Zurn

Division of Surgical Research and Gene Therapy Center, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland

To date, delivery of neurotrophic factors has only allowed to transiently protect axotomized facial motoneurons against cell death. In the present report, long-term protection of these neurons was evaluated by continuously expressing the neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) within the facial nucleus using a lentiviral vector system. The viral vector was injected unilaterally into the facial nucleus of 4-month-old Balb/C mice. In contrast to axotomy in other adult rodents, facial nerve lesion in these animals leads to a progressive and sustained loss and/or atrophy of >50% of the motoneurons. This model thus represents an attractive model to evaluate potential protective effects of neurotrophic factors for adult-onset motoneuron diseases, such as amyotrophic lateral sclerosis. One month after unilateral lentiviral vector injection, the facial nerve was sectioned, and the animals were killed 3 months later. Viral delivery of the GDNF gene led to long-term expression and extensive diffusion of GDNF within the brainstem. In addition, axotomized motoneurons were completely protected against cell death, because 95% of the motoneurons were present as demonstrated by both Nissl staining and choline acetyltransferase immunoreactivity. Furthermore, GDNF prevented lesion-induced neuronal atrophy and maintained proximal motoneuron axons, despite the absence of target cell reinnervation. This is the first evidence that viral-mediated delivery of GDNF close to the motoneuron cell bodies of the facial nucleus of adult mice can lead to complete and long-term protection against lesion-induced cell death.

Key words: axotomy; facial nerve; GDNF; gene expression; gene therapy; gene transfer; lentiviral vector; motoneuron; neuroprotection; neurotrophic factor; Balb/C mice

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20155587-07$05.00/0

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