Because the relative contributions of these mechanisms to neurodegeneration in C9-ALS/FTD are unclear, we sought to develop oligonucleotides that promote RNase H-mediated degradation of pathogenic C9orf72 transcriptional variants that also preserve C9orf72 protein expression and disrupt the production of DPRs. The gene discussed is C9orf72; the disease is amyotrophic lateral sclerosis.