Report Summary

Therapeutic rAAVrh10 Mediated SOD1 Silencing in Adult SOD1G93A Mice and Nonhuman Primates

Study Summary

Overall Study Design 
Amyotrophic lateral sclerosis ALS is a fatal neurodegenerative disease survival in ALS is typically 35 years No 
treatment extends patient survival by more than three months Approximately 20 of familial ALS and 13 of sporadic 
ALS patients carry a mutation in the gene encoding superoxide dismutase 1 SOD1 In a transgenic ALS mouse model 
expressing the mutant SOD1G93A protein silencing the SOD1gene prolongs survival One study reports a therapeutic 
effect of silencing the SOD1 gene in systemically treated adult ALS mice this was achieved with a short hairpin RNA a 
silencing molecule that has raised multiple safety concerns and recombinant adeno-associated virus rAAV 9 We report 
here a silencing method based on an artificial microRNA termed miR-SOD1 systemically delivered using adeno-associated 
virus rAAVrh10 a serotype with a demonstrated safety profile in CNS clinical trials Silencing of SOD1 in adult 
SOD1G93A transgenic mice with this construct profoundly delayed both disease onset and death in the SOD1G93A mice 
and significantly preserved muscle strength and motor and respiratory functions We also document that intrathecal 
delivery of the same rAAVrh10-miR-SOD1 in nonhuman primates significantly and safely silences SOD1 in lower motor 
neurons This study supports the view that rAAVrh10-miR-SOD1 merits further development for the treatment of SOD1-
linked ALS in humans 
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