Members
Yasuto Itoyama (Neurology)
Neurology is one of the fields with high expectations for progress in clarifying the pathomechanisms and developing new therapeutic approaches. Then, the role of the neurologist will become more important now and in the future. Neurological diseases, especially neurodegenerative ones, are often persistently progressive and difficult to treat. We neurologists have an important role in finding effective treatments for the patients.
We were the first to report the copper/zinc superoxide dismutase (SOD1) mutation in familial ALS in Japan, and developed transgenic mice and rats with the SOD mutant gene. The larger size of the rat model facilitates studies towards developing new therapeutic agents. Nowadays, hepatocyte growth factor (HGF) seems to be one of the most promising candidate agents for ALS.
We are making efforts in evaluating several adverse effects of the HGF treatment on primates using marmosets on the way to clinical trials of HGF for ALS patients.
- Introduction of Research
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by selective motor neuron death. Approximately 10% of cases of ALS are inherited, usually as an autosomal dominant trait. In ~25% of familial cases, the disease is caused by mutations in the gene encoding cytosolic copper-zinc superoxide dismutase (SOD1)1). The cause of ALS is still unclear, and clinical trials have as yet failed to identify any truly effective therapeutic regimens for ALS, with only riluzole providing a modest improvement in survival. Various substances have been shown to have therapeutic effects in a murine model of ALS. However, there have been a few reports of prolongation of survival with treatment starting around the time of disease onset. We developed a rat model of ALS expressing a human SOD1 transgene with two ALS-associated mutations: glycine to alanine at position 93 (G93A) and histidine to arginine at position 46 (H46R) 2). Similar to its murine counterpart, this rat transgenic (Tg) ALS model reproduces the major phenotypic features of human ALS. Some experimental manipulations are difficult in Tg mice because of size limitations. However, this Tg rat model allows routine implantation of infusion pumps for intrathecal drug delivery. Intrathecal drug application is a well-established method for therapy and has been used in clinical trials in patients with ALS. This route of administration bypasses the blood?brain barrier, allowing rapid access to potential binding sites for the test compound in the spinal cord
Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. Dr. Funakoshi et al. at Osaka University showed that introduction of the HGF gene into neurons of G93A Tg mice attenuates motor neuron degeneration and increases the lifespan of these mice. Currently, treatment regimens using recombinant protein are closer to clinical application than gene therapy. To examine its both protective effect on motor neurons and therapeutic potential, we administered human recombinant HGF (hrHGF) by continuous intrathecal delivery to G93A Tg rats at doses of 40 or 200 ㎍ and 200 ㎍ at 100 days old (the age at which pathological changes of the spinal cord appear but animals show no clinical weakness) and 115 days old (onset of paralysis), respectivery, for 4 weeks each. Intrathecal administration of hrHGF attenuates motor neuron degeneration and prolonged the duration of the disease by 63 %, even by administration from the onset of paralysis3). Our results indicated the therapeutic efficacy of continuous intrathecal administration of hrHGF in Tg rats, and should prompt further clinical trials in ALS using continuous intrathecal administration of hrHGF.
- Articles
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- 1. Aoki M, Ogasawara M, Matsubara Y et al., Nature Genet. 5:323-324, 1993
- 2. Nagai M, Aoki M, Miyoshi I et al., J Neurosci 21: 9246-54, 2001
- 3. Ishigaki A, Aoki M, Nagai M et al., J Neuropathol Exp Neurol, in press