Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder resulting from selective death of motor neurons in the brain and spinal cord. In approximately 20% of dominantly-inherited familial ALS cases, the disease is caused by mutations in the gene encoding cytosolic Cu,Zn superoxide dismutase (SOD1). The vast majority of ALS-linked variations in SOD1 are point mutations yielding single amino acid substitutions. In cell culture and in rodent models of ALS, mutant SOD1 proteins exhibit dose dependent toxicity; thus, agents that reduce mutant protein expression would be useful therapeutic tools. The overall goal is this project is to evaluate the potential of RNA-mediated interference (RNAi) for silencing expression of mutant SOD1 in vitro and in vivo. Small interfering RNAs (siRNAs) capable of selectively inhibiting expression of mutant SOD1 will be identified. Transgenic mice expressing small hairpin RNAs directed against mutant SOD1 will be generated and crossed to mutant SOD1 transgenic mice; progeny will be monitored for changes in disease onset and progression. In addition, the therapeutic potential of RNAi will be assessed using viral delivery of shRNA to the spinal cords of mutant SOD1 transgenic mice.
| Landers, J E; Leclerc, A L; Shi, L et al. (2008) New VAPB deletion variant and exclusion of VAPB mutations in familial ALS. Neurology 70:1179-85 |
