Wobbler mice

The use of a combination of neurotrophic factors in the treatment of neurodegenerative disease may well prove an avenue worthy of consideration. For example, pre-clinical studies reveal that administration of a combination of CNTF and BDNF to Wobbler mice (an animal model of motor neuron disease), prevented progression of motor neuron dysfuction, whereas administration of either factor on its own only slowed progression of the disease. 

Ciliary neurotrophic factor (CNTF) was also shown to protect wobbler mice, to be required for preservation of adult motor neurons in knockout mice, and to reduce immunoreactivity in the spinal cord of ALS patients. This drug advanced as far as Phase m clinical trials, however, no significant difference in survival was observed betw een CNTF and placebo groups (ALS CNTF Treatment Study Group, 1996 Hurko and Walsh, 2000). 

Mitsumoto, H., Ikeda, K., Klinkosz, B., Cedarbaum, J.M., Wong, V. and Lindsay, R.M. (1994) Arrest of motor neuron disease in wobbler mice cotreated with CNTF and BDNF. Science 265 1107-1110. 

Schmitt-John, T., Drepper, C., Mussmann, A., Hahn, P, Kuhlmann, M., Thiel, C., et al. (2005) Mutation of Vps54 causes motor neuron disease and defective spermiogene-sis in the wobbler mouse. Nat Genet 37, 1213-1215. 

Evidence for neuroinflammation has also been found in other animal models of motor neuron degeneration. Eor example, microglial activation was observed in the Wobbler mouse, a finding that has been confirmed by several groups (Rathke-Hartlieb et al., 1999 Boillee et al., 2001). Elevated TNE- a levels were found in the brain and spinal cord of the mnd mouse (Ghezzi et al., 1998). It appears that these other murine models of motor neuron degeneration share some neu-roinflammatory features with the mSODl model. 

Brain derived neurotrophic factor (BDNF) has been shown to prolong survival, protect against glutamate neurotoxicity, and slow disease progression in the wobbler mouse, an early model of ALS. Unfortunately, BDNF did not show benefit in patients with ALS (Anonymous, 1999). 

Radrke-Hartlieb S, Schmidt VC, Jockusch H, Schmitt-John T, Bartsch JW (1999) Spadolemporal progression of neurodegeneradon and glia acdvadon in die wobbler neuropadiy of die mouse. Neuroreport 10 3411-3416. 

The gene for ciliary neurotrophic factor (CNTF) maps to murine chromosome 19 and its expression is not affected in the hereditary motoneuron disease wobbler of the mouse. Eur. J. Neurosci. 3 1182-1186. 

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