Spacing of the guanidinium charged groups in argininerich CPPs has been extensively studied by Wender et al. (20) and found to be a key determinant of their cellular uptake. A series of (R-X-R) 4 -PMO conjugates with a X linker extending from two to eight atoms have been compared in terms of cellular uptake, splicing correction efficiency and affinity for heparin ( Figure 1B and R. Abes and H. Moulton). As expected, heparin (chosen as a model heparan sulfate) affinity decreased significantly with an increase in X linker length and with a decrease in cationic charges density ( Figure 1B ). In keeping with this observation, cellular uptake as monitored by FACS analysis decreased in parallel ( Figure 4) . However, the ranking of these (R-X-R) 4 -PMO conjugates in terms of splicing correction efficiency had a bell-shaped profile with (R-Ahx-R) 4 -PMO being significantly more efficient than (R-G-R) 4 -PMO ( Figure 1C and data not shown). These observations do strongly suggest that another step than cellular uptake is responsible for differences in splicing correction efficiency among these (R-X-R) 4 -PMO conjugates.