Chemical treatment enhances skipping of a mutated exon in the dystrophin gene

Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease caused by a loss of the dystrophin protein. Control of dystrophin mRNA splicing to convert severe DMD to a milder phenotype is attracting much attention. Here we report a dystrophinopathy patient who has a point mutation in exon 31 of the dystrophin gene. Although the mutation generates a stop codon, a small amount of internally deleted, but functional, dystrophin protein is produced in the patient cells. An analysis of the mRNA reveals that the mutation promotes exon skipping and restores the open reading frame of dystrophin. Presumably, the mutation disrupts an exonic splicing enhancer and creates an exonic splicing silencer. Therefore, we searched for small chemicals that enhance exon skipping, and found that TG003 promotes the skipping of exon 31 in the endogenous dystrophin gene in a dose-dependent manner and increases the production of the dystrophin protein in the patient's cells

Comparative study of straight vs angled incision in 27-gauge vitrectomy for epiretinal membrane

Ryo Yomoda, Hiroki Sasaki, Jiro Kogo, Akira Shiono, Tatsuya Jujo, Reio Sekine, Naoto Tokuda, Yasushi Kitaoka, Hitoshi Takagi Department of Ophthalmology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan Purpose: The purpose of this study was to compare straight and angled incisions in 27-gauge microincision vitrectomy in patients with epiretinal membrane (ERM).Methods: Seventy-three eyes of 68 patients with ERM who underwent straight (35 eyes) or angled incision (38 eyes) for 27-gauge microincision vitrectomy were retrospectively evaluated.Results: No statistically significant difference was found between the two groups in postoperative logarithm of minimal angle of resolution best-corrected visual acuity. The intraocular pressure and rate of hypotony 1 day postoperatively did not differ between the straight- and angled-incision groups (intraocular pressure: 11.5 vs 13.4 mmHg, respectively; rate of hypotony: 20% vs 8%, respectively). Surgical wound closing occurred by postoperative day 10 in both groups.Conclusion: A straight incision is as safe and useful in ERM vitrectomy as an angled one. Keywords: 27-gauge vitrectomy, MIVS, epiretinal membrane, straight incision, angled incision, anterior segment OCT&nbsp

Small-molecule pyrimidine inhibitors of the cdc2-like (Clk) and dual specificity tyrosine phosphorylation-regulated (Dyrk) kinases: Development of chemical probe ML315

Substituted pyrimidine inhibitors of the Clk and Dyrk kinases have been developed, exploring structure-activity relationships around four different chemotypes. The most potent compounds have low-nanomolar inhibitory activity against Clk1, Clk2, Clk4, Dyrk1A and Dyrk1B. Kinome scans with 442 kinases using agents representing three of the chemotypes show these inhibitors to be highly selective for the Clk and Dyrk families. Further off-target pharmacological evaluation with ML315, the most selective agent, supports this conclusion