Exon edited dystrophin rods in the hinge 3 region

We have studied the properties of a panel of proteins engineered to be end-products of envisioned exon skipping therapy by antisense oligonucleotides, AONs, directed at exon 51 applied to relevant dystrophin defects causing Duchenne muscular dystrophy, DMD. Exon skipping therapy is a leading therapeutic strategy being investigated for the treatment of this devastating genetic disease. AONs targeting exon 51 have progressed furthest in human clinical trials. Exon 51 skipping is applicable to a variety of dystrophin defects found in different patients. Due to the differences in original defect, the end result of the therapy will be different in each case. An open question is whether these differences will produce significant differences in the dystrophin protein so edited. In this study we have identified differences in the stability, structure and lipid binding properties of these end-product proteins produced by exon 51 skipping repair.

► Exon skipping repair is a leading therapeutic hope for Duchenne muscular dystrophy. ► Skipping of exon 51 has been tested in boys with various relevant gene defects. ► The final repair is a combination of the original defect and the therapeutic skip. ► We studied 4 different such repairs to assess their fidelity to native dystrophin. ► 2 of the 4 show significantly perturbed structure or function.