The above studies have helped make it clear that unnatural amino acids can confer enhanced stability and activity, and therefore improve the potential of CPPs to deliver therapeutic PMO. In pursuit of CPPs with improved characteristics, we have carried out a structure-activity relationship study to investigate the effects of unnatural amino acid insertions in oligoarginine peptides on cellular delivery, nuclear antisense activity, toxicity and serum-binding characteristics of the resulting CPPÀPMO conjugates. The unnatural amino acids studied here are X, B and D-arginine (r). We chose to study the X amino acid based on the successes of the (RXR) 4 CPP in several studies as shown in the previous paragraph. B and r amino acids were chosen because they have good enzymatic stability (5) . The CPPs are (i) the oligoarginine sequences, R 8 and R 9 , (ii) sequences with RXR, RX and RB repeats, as well as various combinations thereof, and (iii) sequences containing D-arginine, r 8 , (rX) 8 (rXR) 4 , (rXr) 4 and (rB) 8 . The CPPÀPMO conjugates were evaluated for their relative (a) cellular uptake, as determined by flow cytometry, (b) antisense activity, as determined by a splice correction assay (13) and (c) cellular toxicity, as determined by MTT cell viability, propidium iodide membrane integrity and hemolysis assays, as well as by microscopic imaging.