2026-06-25 | Generation of isogenic rescue iPSC lines by targeted CTG-repeat excision for myotonic dystrophy type 1.
An expanded CTG repeat in the Dystrophia Myotonica Protein Kinase (DMPK) gene is associated with myotonic dystrophy type 1 (DM1), an autosomal dominant neuromuscular disorder characterised by progressive muscle weakness, myotonia, cognitive decline, and a variety of other manifestations. Here, we report the generation of isogenic induced pluripotent stem cell (iPSC) lines, derived from patient DM1 iPSC lines carrying varying expanded (CTG)n repeats in DMPK. These gene-edited isogenic iPSC lines, in which the pathogenic repeat has been excised, serve as a reference for assessing DM1-associated phenotypes in relevant differentiated cell types, such as muscle progenitor cells and neurons.
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2026-06-24 | Bottlebrush polymer conjugates for enhanced antisense oligonucleotide therapy in myotonic dystrophy type 1.
Oligonucleotides are a promising class of genetic medicine for myotonic dystrophy type 1 (DM1), the most common adult-onset muscular dystrophy. However, poor muscle distribution of nucleic acid drugs following systemic administration has hindered drug development, and no curative treatment currently exists. DM1 pathology requires drug localization to the nucleus, where pathogenic mutant RNA is sequestered, posing additional challenges after cellular internalization regarding endosomal escape and nuclear uptake. Here, we show that a locked nucleic acid oligonucleotide targeting mutant CUG repeat RNA tracts, conjugated to a bottlebrush polymer, exhibits improved muscle distribution and potent correction of DM1-associated splicing dysregulation in a DM1 mouse model. Significant improvements in myotonia, body weight, and grip strength were observed. The conjugate was well tolerated following 12 weeks of weekly intravenous administration. These findings suggest that bottlebrush polymer conjugates may overcome key limitations of conventional oligonucleotide therapeutics for neuromuscular conditions, with potential to become a potent and cost-effective DM1 therapy.
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2026-06-23 | Hypericin repairs misregulated splicing events associated with myotonic dystrophy in type 1 myoblast lines
Myotonic dystrophy is associated with the molecular event of misregulated splicing of a subset of RNAs, which contribute to some of the disease phenotypes. One of the misregulated splicings that leads to one of the disorder’s phenotypes is insulin resistance (IR). Other misregulated splicing events considered in this study included Sarcoplasmic Endoplasmic Reticulum ATPase 1 (SERCA1), and muscleblind protein isoforms 1 and 2 (MBNL1 and MBNL2). Assays based on the above splicing events were designed for reverse transcription (RT-PCR) analysis and applied to myotonic dystrophy type 1 (DM1) myoblasts derived from differentiated fibroblasts to test for a compound that could reverse misregulated splicing in the cultures. Reverse Transcribed PCR methods quantified by the Genescan genetic analyser were utilised for the study. In this study, hypericin, a protein kinase C inhibitor, was observed to affect a slight reversal of misregulated splicing associated with the disorder in the insulin receptor (IR) by enhancing the relative proportion of the muscle signalling type (IR-B) in myotonic dystrophy type 1 myoblasts. Additionally, hypericin increased the proportion of the skeletal muscle isoform (SERCA1a) in DM1 myoblast cultures compared with mock control (DMSO-treated) (p=0.002). Furthermore, hypericin treatment was also observed to correct missplicing in MBNL1 and MBNL2 by reducing the proportion of isoforms containing exon 7. In this study, hypericin treatment corrected splicing abnormalities in all splicing assays performed in DM1 myoblasts. Taken together, the results indicate that hypericin may have therapeutic potential in the DM1 cell model used in this study.
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