The invention includes methods for predicting whether an antisense oligonucleotide (ASO) will be efficacious for inhibiting expression of a gene. The invention also includes methods of making efficacious ASOs, comprising a 5'-TCCC-3' motif or another chemical entity which is capable of Watson-Crick-type base-pairing with a 5'-GGGA-3' motif in an RNA molecule such as a primary transcript or an mRNA. The invention further includes ASOs which are useful for inhibiting expression of one of tumor necrosis factor-a in a mammal. Methods of treating an animal comprising a disease or disorder which is characterized by the presence of an RNA molecule in a cell of the animal are also included.