title: [Amyotrophic lateral sclerosis with the SOD1 mutations].
abstract: Mutations in Cu/Zn superoxide dismutase (SOD1) have been linked to some familial cases of amyotrophic lateral sclerosis (ALS). In familial ALS kinders with mutations in the SOD1 gene, the age of onset of weakness varies greatly but the duration of illness appears to be characteristic to each mutation. For example, in patients with the L84V mutation, the average life expectancy is less than 1.5 year after the onset of symptoms, whereas patients harboring the H46R mutation have an average life expectancy of 18 years after the disease onset. In view of the evidence supporting the idea that familial ALS variants of SOD1 enzymes acquire toxic properties, the variations in the duration of illness in the different kinders might arise because each mutation imparts different degrees of toxicity to the mutant protein. We developed rats that express a human SOD1 transgene with two different ALS-associated mutations (G93A and H46R) develop striking motor neuron degeneration and paralysis. The larger size of this rat model as compared with the ALS mice will facilitate studies involving manipulations of spinal fluid (implantation of intrathecal catheters for chronic therapeutic studies; CSF sampling) and spinal cord (e.g., direct administration of viral- and cell-mediated therapies). Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. To examine its both protective effect on motor neurons and therapeutic potential, we administered human recombinant HGF (hrHGF) by continuous intrathecal delivery to G93A transgenic (Tg) rats at onset of paralysis for 4 weeks. Intrathecal administration of hrHGF attenuates motor neuron degeneration and prolonged the duration of the disease by 63%. Our results indicated the therapeutic efficacy of continuous intrathecal administration of hrHGF in Tg rats. The results should prompt further clinical trials in ALS using continuous intrathecal administration of hrHGF.
authors.affiliation: Department of Neurology, Tohoku University School of Medicine, Tohoku University Hospital ALS Center.
authors.forename: Masashi
authors.initials: M
authors.lastname: Aoki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Warita
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Itoyama
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage; D006801:Humans; D007278:Injections, Spinal; D051379:Mice; D009154:Mutation; D051381:Rats; D055647:Rats, Transgenic; D011994:Recombinant Proteins / Q000008:administration & dosage; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: D011994:Recombinant Proteins; C000606290:SOD1 protein, human; D017228:Hepatocyte Growth Factor; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1