A strategy for developing effective amyotropic lateral sclerosis pharmacotherapy: from clinical trials to novel pharmacotherapeutic strategies.
BACKGROUND
The pathomechanism of sporadic amyotropic lateral sclerosis is not clearly understood, although a proportion of familial amyotropic lateral sclerosis is caused by superoxide dismutase 1 mutations. Theories based on studies of human post-mortem tissue, research on animal models and in vitro work have been proposed for the pathogenesis of amyotropic lateral sclerosis, but the pathogenesis is not the same between sporadic and familial amyotropic lateral sclerosis.


OBJECTIVE
Drug candidates were tested using superoxide dismutase 1 mutant mice. Although the candidates were shown to be effective in mice, clinical trials in humans have failed to identify any truly effective pharmacotherapies in sporadic amyotropic lateral sclerosis, with only riluzole providing a modest improvement in survival. Ongoing or planned trials are exploring the value of antiglutamatergic drugs, antioxidants, neurotrophic factors, anti-inflammatory drugs and anti-aggregation drugs.


CONCLUSIONS
A combination of drugs acting on different mechanisms is needed for effective therapy. Moreover, gene expression profiling and genome-wide association studies, together with inhibitory RNA techniques, are helpful for developing new pharmacotherapeutic strategies including gene therapy. It is also likely that the recently advanced generation of induced pluripotent stem cells will lead to the development of cell therapy for amyotropic lateral sclerosis. In addition to finding effective therapies, research is also needed in order to detect early disease markers since pharmacotherapy is most beneficial when given early in the course of sporadic amyotropic lateral sclerosis.
Yamamoto
Masahiko
M
Nagoya University Graduate School of Medicine, Department of Neurology, Nagoya 466-8550, Aichi, Japan.
Tanaka
Fumiaki
F
Tatsumi
Hiroshi
H
Sobue
Gen
G
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D015195:Drug Design; D020869:Gene Expression Profiling; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D009154:Mutation; D033581:Stem Cell Transplantation; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D013997:Time Factors
C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1