DMD exon skipping trial using a 2OMeAO was halted as primary and secondary endpoints were not met. While disappointing for the DMD community, these trial results cannot be regarded as surprising as there had been no unequivocal increases in dystrophin after 2OMe AO treatment. In contrast, another DMD exon skipping trial using an oligomer composed of the PMO chemistry appears to have stabilized ambulation in 10 out or 12 trial participants, with robust dystrophin being detected in muscle biopsies from these boys. A previous study by Fong and colleagues employed another splice switching oligonucleotide chemistry, 29-methoxy-ethyl modified bases on a phosphorothioate backbone to activate the cryptic splice site in normal human fibroblasts. Their most effective AO targeted 34 to 56 bases downstream of the HGPS cryptic splice site, whereas in this study two other domains downstream to the cryptic splice site were most efficient in inducing progerin. Another difference between this study and that by Fong et al, is that our study identified a wider area that can mediate progerin expression. Further, whereas a seemingly precise switching from lamin A to progerin production was achieved by Fong et al, variable degrees of exon 11 skipping invariably accompanied increased utilization of the cryptic site in our study with 2OMe AOs. For example, the 2OMe AO 11A has the same sequence as one of the most efficient AOs described by Fong et al., and caused both cryptic splice site activation and exon 11 skipping in our study. Several factors may contribute to the discrepancies between the two studies, including the use of different cell strains and different AO chemistries. However, we also transfected normal human skin fibroblasts with our AOs and the resulting splicing pattern was identical to that induced in myogenic cells. It is therefore unlikely that splicing environment in different tissues is responsible for the disparity in splicing redirection in the different studies. The variable efficiencies with which progerin was induced by our 2OMe AOs and PMOs also support the possibility that the oligonucleotide chemistry has a major impact on transfection outcomes. But other factors may also contribute: different AO length, transfection concentrations and PCR amplification conditions. We could induce the accumulation of progerin as well as lamin A DE11 in human myogenic cells using splicing switching AOs. Both progerin and lamin A DE11 lack a proteolytic site for posttranslational modification of the precursor protein prelamin A. Consequently, both aberrant proteins retain a farnesyl group at the C terminal, which is normally cleaved from the wild-type mature lamin A. It is proposed that the farnesyl group plays a key role in the pathogenesis of farnesylated prelamin A-accumulating diseases. The retention of the farnesyl group prevents the progerin from disassociating from the nuclear lamina during the cell cycle and disrupts mitosis.