What is Exon Skipping and can it be used to treat LGMD2B?

Genes are the instructions manuals that tell the cell how to make the proteins that are needed for the cell to function properly.   When there is an error in those instructions (i.e. a mutation in the gene), the cell is unable to make its corresponding product (i.e. the protein) and this results in a disease.    If the part of the gene containing the error can be skipped, a slightly smaller but potentially functional protein could be made.   The parts of the gene that make the protein are called “exons” and each protein is encoded by multiple exons.  “Exon skipping” refers to the therapeutic technique by which one or more of the protein coding exons is “skipped” in order remove the mutation that is causing the disease and allow for the protein to be made.   For a simplified explanation of exon skipping, click here. Exon skipping has been assessed in several clinical trials as a possible treatment for Duchenne muscular dystrophy (DMD).  In the DMD studies, exon skipping has been shown to be relatively safe and has demonstrated some effectiveness in treating the disease (click here for more information). 

 

The question is whether “exon skipping” is a possible therapy for all forms of muscular dystrophy.  DMD is a very good candidate for the exon skipping approach because there is preexisting knowledge that dystrophin can function when truncated and there is a commonly mutated region of the gene.  DMD is caused by mutations in the dystrophin gene that result in the complete absence of the dystrophin protein.  There is a milder form of the disease called Becker muscular dystrophy (BMD) which is also caused by mutations in dystrophin, but the BMD mutations “skip” one or more exons and make a smaller form of the protein that is at least partially functional.   Researchers reasoned that if a truncated form of dystrophin could be made in DMD patients by skipping mutated exons, a less severe form of muscular dystrophy, like Becker, could result.  In addition, it is estimated that about 13% of boys with DMD have mutations in a single location of the dystrophin gene (exon 51); therefore a considerable number of DMD patients can be treated with the development of just one exon skipping strategy. 

 

It is more difficult to predict whether exon skipping is a logical therapy for dysferlinopathy (LGMD2B/Miyoshi), which is caused by mutations in the dysferlin gene that cause the absence of dysferlin protein. Unlike dystrophin, it is not known whether particular regions of the dysferlin gene are essential to make a functional protein or if any truncated dysferlin proteins will be functional. This information will be necessary prior to designing exon skipping strategies.   Also unlike DMD in which mutational “hot spots” suggest logical exons for skipping, patients with dysferlinopathy (LGMD2B/Miyoshi) have mutations across the entire dysferlin protein, with no significant concentration of mutations in any particular exons.  Therefore, multiple exon skipping strategies would have to be designed and tested for a significant number of patients to be helped, which is likely to cause regulatory hurdles and delay the availability of treatment. 

 

Given these issues, there is a considerable amount of research that still needs to be done to assess whether exon skipping will be a viable therapeutic option for dysferlinopathy and the Jain Foundation is exploring ways to help with this analysis.   An important point to note regarding the application of exon skipping as a therapeutic option is that each individual needs to know their exact mutations in the dysferlin gene to determine whether “exon skipping” would be benefical.  If you are unsure whether or not you have been genetically diagnosed the Jain Foundation can help.  Please contact the Jain Foundation’s Director of Patient Relations, Sarah Shira, at  or 425-882-1440 or click here for more information.