Recently, we showed that a small molecule, CB253 (Figure ), targeting r(G4C2) hexanucleotide repeat expansions associated with ALS/FTD can cause strand-slippage to transform the global RNA structure to an alternative form, which has 2×2 GG/GG internal loop motifs . This internal loop motif is both transient and highly dynamic displaying rapid 1×1 G/G ↔ 2×2 GG/GG transformations, which prevents its characterization by traditional biophysical techniques. F NMR studies utilizing F modified cytidine residues in closing base pairs indicate that 1×1 G/G and 2×2 GG/GG internal loop motifs formed 70% and 30%, respectively, in the absence of CB253 (Figure ) . In vitro experimental studies also showed that 2×2 GG/GG was preferred by r(G4C2) exp in the presence of CB253 . This observation provides a new direction in targeting r(G4C2) exp with small molecules that can inhibit the pathobiological effects driven by this expanded repeat. Nevertheless, little is known about the properties of 2×2 GG/GG internal loops.