Amyotrophic lateral sclerosis (ALS) is a fatal disease caused by motor neuron degeneration and resulting muscle wasting. The ~6,000 new cases of ALS in the US each year afflicts those >40 years of age. There is no effective treatment for ALS and those who contract the disease die 2-5 years after diagnosis. Most causes of ALS are unknown, but the most common known genetic cause is an aberrant C9ORF72 gene. Within this gene, a DNA GGGGCC hexanucleotide sequence is reiterated perhaps thousands of times, which causes the disease. This G4C2 expansion is transcribed into RNA that in turn generate dipeptide repeat proteins (DPRs), whose toxicity is thought to promote motor neuron degeneration. We have identified regions in C9ORF72 RNA that are the start sites for DPR synthesis. These start (ribosome initiation) sites can be occluded by binding to complementary DNA antisense oligonucleotides (AS-ODNs), which are modified to readily enter cells of the nervous system and stably and specifically bind their target sequences in C9ORF72 RNA. Such AS-ODNs would inhibit DPR production, thereby slowing or inhibiting disease progression. We propose to use human disease neurons in culture and C9ORF72 model mice to test the efficacy and specificity of AS-ODNs to inhibit DPR synthesis and mitigate ALS pathophysiology.