Amyotrophic lateral sclerosis (ALS) is an adult-onset, lethal, paralytic disorder caused by the degeneration of motor neurons. Our understanding of this disease has been greatly facilitated by studies of familial ALS caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Evidence indicates that misfolded wild-type SOD1 may also be pathogenic in sporadic ALS. Mutant SOD1 is neurotoxic through multiple mechanisms. Because the pathogenicity of mutant SOD1 is proportional to the dose of the toxic protein, a rational approach to treating SOD1-related ALS is to reduce levels of the toxic SOD1 species. An advantage of this strategy is that it potentially obviates intervening in multiple, downstream pathological cascades. In recent years, several strategies to silence gene expression have been developed. The most clinically promising are predicated on approaches that enhance degradation of RNA, such as anti-sense oligonucleotides (ASO) and RNA interference (RNAi); the latter include small inhibitory RNA (siRNA), short hairpin RNA (shRNA) and microRNA (miR). Agents such as shRNA and either native or synthetic miR are capable of permeating the central nervous system (CNS) and efficiently silencing genes in the brain and spinal cord. Here we review recent progress in silencing SOD1, focusing on studies using artificial shRNA or miRNA in combination with potent viral vector delivery systems to mediate SOD1 silencing within the CNS in transgenic SOD1G93A mice and non-human primates.
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