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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32NS048809-01
Application #
6791917
Study Section
Special Emphasis Panel (ZRG1-F01 (20))
Program Officer
Refolo, Lorenzo
Project Start
2004-04-01
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
1
Fiscal Year
2004
Total Cost
$47,296
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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