Annemieke Aartsma-Rus, Department of Human Genetics, Leiden University Medical Center
9 August 2007
We have previously reported similar findings (Mol Ther 2006, 14(3):401-7, Aartsma-Rus et al. “Exploring the frontiers of therapeutic exon skipping for Duchenne muscular dystrophy by double targeting within one or multiple exons.”
http://www.nature.com/mt/journal/v14/n3/abs/mt20061311a.html). In the study described there we have analyzed the effect of using combinations of AONs for exons that were not, poorly and efficiently skippable with individual AONs. We observed that using non overlapping AONs high skipping levels of previously unskippable exons 47 and 57 could be induced. In addition, skipping levels were significantly enhanced for the poorly skippable exon 45. However, combining AONs targeting exons that could already be efficiently skipped with single AONs did not further improve exon skipping levels. Notably, using overlapping AONs never induced exon skipping, regardless of whether individual AONs were effective or not.
Finally, the authors note that SC35 seem to be overrepresented in effective AON cocktails. We have previously compared SC35 target sites in effective and ineffective AONs and observed that SC35 target sites were significantly (p-value 0.03) overrepresented in effective AONs (Oligonucleotides 2005, 15(4):284-97, Aartsma-Rus et al. “Functional analysis of 114 exon-internal AONs for targeted DMD exon skipping: indication for steric hindrance of SR protein binding sites.” http://www.liebertonline.com/doi/abs/10.1089/oli.2005.15.284).
Additional results with double targeting
9 August 2007
We have previously reported similar findings (Mol Ther 2006, 14(3):401-7, Aartsma-Rus et al. “Exploring the frontiers of therapeutic exon skipping for Duchenne muscular dystrophy by double targeting within one or multiple exons.”
http://www.nature.com/mt/journal/v14/n3/abs/mt20061311a.html). In the study described there we have analyzed the effect of using combinations of AONs for exons that were not, poorly and efficiently skippable with individual AONs. We observed that using non overlapping AONs high skipping levels of previously unskippable exons 47 and 57 could be induced. In addition, skipping levels were significantly enhanced for the poorly skippable exon 45. However, combining AONs targeting exons that could already be efficiently skipped with single AONs did not further improve exon skipping levels. Notably, using overlapping AONs never induced exon skipping, regardless of whether individual AONs were effective or not.
Finally, the authors note that SC35 seem to be overrepresented in effective AON cocktails. We have previously compared SC35 target sites in effective and ineffective AONs and observed that SC35 target sites were significantly (p-value 0.03) overrepresented in effective AONs (Oligonucleotides 2005, 15(4):284-97, Aartsma-Rus et al. “Functional analysis of 114 exon-internal AONs for targeted DMD exon skipping: indication for steric hindrance of SR protein binding sites.” http://www.liebertonline.com/doi/abs/10.1089/oli.2005.15.284).
Competing interests
None declared