CureDuchenne - Together we Can CureDuchenne
September 2012

Exon Skipping Strategies for the Treatment of Duplication Mutations in Duchenne Muscular Dystrophy

Exon skipping test mouse
A new colony of lab mice are being bred
to study exon skipping as a possible
treatment for Duchenne muscular dystrophy.

Our knowledge of exon skipping has evolved over recent years to the point where the first drugs targeting a single exon are poised for approval. This will benefit a sub group of boys with deletions that can be helped by an exon 51 skipping drug.

However, a significant number of our boys have duplicated exons; and while the science of exon skipping has continued to mature, drug development programs have not yet begun to target this population of boys. CureDuchenne has invested in cutting edge science to bridge this gap by supporting the development of a critically needed new in vivo mouse model, as well as in vitro assays in human cell lines that will help accelerate the development of new strategies for the skipping of duplicated exons.

Two AON exon skipping drugs are currently being studied in late-stage clinical trials for deletion mutations associated with exon-51. These drugs target and skip a single exon only, and expectations are high for the first one to be approved within the next few years. This will be followed in subsequent years with additional AON drugs targeting deletion mutations associated with other exons.

A flurry of recent publications have highlighted successful multiple exon skipping in dystrophic mice and dogs that open the door to being able to treat a broader patient population with deletion mutations as well as the ability to target a subset of DMD patients that harbor one or more duplicated exons.

Unfortunately, no preclinical animal model of DMD is known to harbor a duplicated exon. To this end, CureDuchenne partnered with Dr. Kevin Flanigan and colleagues at Nationwide Children’s Hospital at Columbus, to support the development of the first mouse model in which an exon is duplicated. This is intended to offer a platform for in vivo testing of duplication strategies for the first time and our goal is to make the model available to the broader research community. This mouse model carries a duplication of exon 2 within the Dmd locus (mdxdup2 mouse) as this mutation represents the most common human duplication and additionally it results in a relatively severe DMD.

The group have recently succeeded in producing for the first time, male mouse pups that carry a confirmed tandem exon 2 duplication (RT-PCR analysis), and they are currently expanding this mouse colony in order to provide enough animals for detailed analysis and future studies.

They expect to establish the phenotype of the mdxdup2 mouse early next year, assessing dystrophin expression in skeletal muscle, as well as assessing the severity of muscle disease using physiological and pathological assessments as the mice grow and mature. Once adequate numbers of male mdxdup2 mice are available, the group will immediately begin (for the first time) the key exon skipping studies using both antisense oligomers as well as U7 snRNA in an exon-duplication model. But this is only the beginning.

In addition to the new mdxdup2 mouse model, CureDuchenne is supporting the group to develop and characterize patient-derived fibroblast cell lines representative of a broad variety of duplicated exons. This critically important step will add to our knowledge of skipping duplicated exons from patient derived cells and will allow us to test the effectiveness of different exon skipping strategies, as well as the efficiency of U7 snRNA-mediated exon skipping on human duplication mutations.