Summary and Future Direction

Antisense-mediated exon skipping aims to reframe dystrophin transcripts to allow generation of partly functional proteins and conversion of a severe Duchenne into a milder Becker phenotype. The first proof-of-concept in patient-derived cells was obtained in 2001 (van Deutekom et al. 2001), and the first clinical trial in DMD patients was conducted in 2006 (van Deutekom et al. 2007). This is relatively fast, especially given that AONs are a new type of drug. There are several reasons why AONs are now closer to clinical application than some of the more traditional therapeutic approached like gene and cell therapy. The exon skipping approach modulates endogenous pre-mRNA transcripts using synthetic DNA/RNA analogs. This eliminates the risks of an immune response towards viral vectors, donor-derived or autologous ex vivo modified cells and/or insertional mutagenesis. In addition, delivery of small AONs is very efficient, especially in dystrophic muscle, while efficient delivery of genes without a viral vector system or through cell transplantation needs further optimization.

An immune response to the newly generated dystrophin is unlikely. First, in the majority of patients spontaneous exon skipping and reframing of dystrophin transcripts takes place at a very low level, resulting in occasional dystrophin positive revertant fibers (Fanin et al. 1992). The amount of these dystrophin positive fibers is not sufficient to prevent the progressive deterioration in muscle quality . However, it does mean that for most patients dystrophin will not be a neo-antigen. In addition, the N-terminal part (up to the mutation) of dystrophin will still be produced and dystrophin has several C-terminal isoforms as well and generally not all of these are affected by the mutation.

One of the disadvantages of the approach is that due to AON and protein turnover, treatment is not permanent and will have to be repeated. Nevertheless, AONs are new types of drugs, that are still being further developed and for which no long-term treatment data is yet available. Thus, it is not so bad that treatment can be stopped should there be any unforeseen toxic effects due to long-term AON exposure, or should a more efficient AON chemistry be identified the original treatment can be replaced by the more optimal treatment.

The exon skipping approach can be seen as personalized medicine, as it is tailored to the need of different patients with varying mutations (van Ommen et al. 2008). Despite the current hype about personalized medicine, the biggest challenge for clinical application of exon skipping is that regulatory offices are not yet ready for these types of drug. AONs targeting different exons are considered different drugs, but this is also the case for AONs targeting different sequences in the same exon and even for AONs targeting the same sequence but with different backbone chemistries. Given that DMD is a rare disease and that the largest group of patients (requiring exon 51 skipping) consists of only 13% of all patients, multicenter studies are needed already for early stage clinical trials to allow inclusion of sufficient numbers of patients. While it is true that each AON consists of a unique combination of nucleotides, and thus each carries the possibility to induce unique side effects, the chemistry-specific side effects will be similar for all AONs of the same backbone. For some exons the groups that benefit are very small, sometimes limited to one or two patients worldwide, making later phase clinical trials for these AONs impossible (van Ommen et al. 2008). Thus, new ways to properly test the safety of these drugs in patients have to be devised to prevent that treatment development is limited only to patients with "common" mutations due to an incompatibility with the rules and regulations.

Acknowledgement Annemieke Aartsma-Rus is funded through a grant from ZonMw (the Netherlands). Annemieke Aartsma-Rus and Gert-Jan van Ommen have 1 and 2 patents on exon skipping, respectively.

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