Cell-mediated exon skipping normalizes dystrophin expression and muscle function in a new mouse model of Duchenne Muscular Dystrophy.

Cell therapy for muscular dystrophy has met with limited success, mainly due to the poor engraftment of donor cells, especially in fibrotic muscle at an advanced stage of the disease. We developed a cell-mediated exon skipping that exploits the multinucleated nature of myofibers to achieve cross-correction of resident, dystrophic nuclei by the U7 small nuclear RNA engineered to skip exon 51 of the dystrophin gene. We observed that co-culture of genetically corrected human DMD myogenic cells (but not of WT cells) with their dystrophic counterparts at a ratio of either 1:10 or 1:30 leads to dystrophin production at a level several folds higher than what predicted by simple dilution. This is due to diffusion of U7 snRNA to neighbouring dystrophic resident nuclei. When transplanted into NSG-mdx-Δ51mice carrying a mutation of exon 51, genetically corrected human myogenic cells produce dystrophin at much higher level than WT cells, well in the therapeutic range, and lead to force recovery even with an engraftment of only 3-5%. This level of dystrophin production is an important step towards clinical efficacy for cell therapy.

Acquired haemophilia: an easy diagnosis to miss in a patient taking warfarin.

Acquired Haemophilia (AH) is an autoimmune bleeding disorder, which despite being rare, can be fatal. It occurs in patients with previously normal haemostasis who spontaneously develop IgG autoantibodies against factor VIII. Unlike congenital haemophilia, it manifests as spontaneous bleeding into skin and soft tissues. The presentation can be masked in patients who are receiving warfarin where the bleeding is often attributed to warfarin therapy, as in the case described in this report. Consideration of AH is important in patients taking anticoagulants, when coagulopathy and bleeding fails to correct with usual measures.