Abstract:

Objective   To investigate the therapeutic effects of the human glial cell line-derived neurotrophic factor (GDNF) gene in a mouse model of amyotrophic lateral sclerosis (ALS).  Methods   ALS mice with the SOD1G93A mutation were randomly divided into an AdCMVlacz control group and an AdCMVgdnf treatment group (each of 12 mice). ALS mice were given AdCMVgdnf by intramuscular injection at 9 weeks of age. Motor strength and coordination were evaluated with the Rotarod test, beginning at 10 weeks of age.  The time of disease onset and the longevity of the  mice were recorded. Expression of GDNF in muscle and spinal cord at 16 weeks of age were detected by ELISA and immuno histochemical staining. The spinal cord motor neurons and skeletal muscles were also quantitatively analyzed. Results   ①The level of GDNF expression in injected muscle was （6589.0±325.0 ）pg/mg in the treatment group, which was about 100 times more than in the control group (75.3±18.9) pg/mg（P<0.01). ② The weight of the gastrocnemius was （88.6±14.5） mg in control group, and （174.9±18.7 ）mg in the treatment group, the difference being significant (P<0.01). ③ In the spinal cord, both the GDNF level and the motor neuron number in the treatment group were higher than in the control group (P<0.01). ④ Disease onset was delayed（ 123.0±6.9） days of age in the treatment group as compared with（ 96.2±5.8 ）days in the control group (P<0.01).  The mice′s longevity in the treatment group was （155.2±4.1） days as compared with（ 127.3±4.6） days in the control group (P<0.01).  Conclusions   Gene therapy for ALS model mice  using AdCMVgdnf resulted in neuroprotective effects on spinal motor neurons, and significant improvement in skeletal muscle atrophy and neurological movement.   Disease onset was delayed and longevity was prolonged.

Key words: Amyotrophic lateral sclerosis; Gene therapy; Glial cell line-derived Neurotrophic factor; Adenovirus; Motor neurons