Mutations in SOD1 cause approximately 2% of amyotrophic lateral sclerosis (ALS), an adult onset neurodegenerative disease characterized by loss of motor neurons resulting in severe weakness, muscle atrophy, and death typically in 3-5 years secondary to failure of respiratory muscles. Animal models and human studies suggest that lowering levels of SOD1 would be protective. We have developed antisense oligonucleotides that lower SOD1 in the brain and spinal cord when delivered to the cerebral spinal fluid. One of these antisense oligonucleotides was tested in a Phase I human clinical trial and demonstrated excellent safety at the low doses tested. However, it is clear from subsequent studies that we need to develop new antisense oligonucleotides for human SOD1. The collaborative work between Timothy Miller, Merit Cudkowicz and Isis Pharmaceuticals outlined in this grant will define a more potent, safer SOD1 antisense oligonucleotide by performing toxicology studies in rodents and non-human primates and by testing efficacy in the SOD1G93A rat studies. The successful completion of these studies will lead to an IND for the new SOD1 antisense oligonucleotide for SOD1-related ALS.
There are no adequate therapies for SOD1-related ALS or sporadic ALS and thus these efforts may define a new therapy for a devastating untreatable disorder. In addition, the research strategy being pioneered here is likely to apply to C9orf72-related ALS as well as many other neurodegenerative syndromes for which an mRNA target has been identified.