AI Article Synopsis
- - Vascular Ehlers-Danlos syndrome (vEDS) is a serious connective tissue disorder marked by skin elasticity issues, joint hypermobility, and risks of deadly vascular ruptures due to specific collagen III mutations.
- - The study investigated using antisense oligonucleotides (ASOs) to modify pre-mRNA and bypass these mutations, leading to successful excision of specific exons (10 and 15) and increased collagen III expression in patient fibroblasts.
- - Although the ASOs effectively skipped the target exons, the resulting collagen III showed problems with extracellular matrix formation, indicating that post-translational modifications are critical to proper collagen assembly and raising questions about the approach's therapeutic potential. *
Article Abstract
Vascular Ehlers-Danlos syndrome or Ehlers-Danlos syndrome type IV (vEDS) is a connective tissue disorder characterised by skin hyperextensibility, joint hypermobility and fatal vascular rupture caused by mutations that affect collagen III expression, homo-trimer assembly and secretion. Along with collagens I, II, V and XI, collagen III plays an important role in the extracellular matrix, particularly in the inner organs. To date, only symptomatic treatment for vEDS patients is available. Fibroblasts derived from vEDS patients carrying dominant negative and/or haploinsufficiency mutations in deposit reduced collagen III in the extracellular matrix. This study explored the potential of an antisense oligonucleotide (ASO)-mediated splice modulating strategy to bypass disease-causing mutations reported in the in-frame exons 10 and 15. Antisense oligonucleotides designed to redirect pre-mRNA processing and excise exons 10 or 15 were transfected into dermal fibroblasts derived from vEDS patients and a healthy control subject. Efficient exon 10 or 15 excision from the mature mRNA was achieved and intracellular collagen III expression was increased after treatment with ASOs; however, collagen III deposition into the extracellular matrix was reduced in patient cells. The region encoded by exon 10 includes a glycosylation site, and exon 15 encodes hydroxyproline and hydroxylysine-containing triplet repeats, predicted to be crucial for collagen III assembly. These results emphasize the importance of post-translational modification for collagen III homo-trimer assembly. In conclusion, while efficient skipping of target exons was achieved, the induced collagen III isoforms generated showed defects in extracellular matrix formation. While therapeutic ASO-mediated exon skipping is not indicated for the patients in this study, the observations are restricted to exons 10 and 15 and may not be applicable to other collagen III in-frame exons.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11354334 | PMC |
| http://dx.doi.org/10.3390/ijms25168816 | DOI Listing |
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