Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA169527 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description: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.
2026-07-01 | GSE309640 | GEO
Project description:MEG3 Upregulation in Myotonic Dystrophy and Its Correction by Antisense Conjugates Targeting Disease-Causing Mutations [miRNA-seq]
| PRJNA1090496 | ENA
Project description:MEG3 Upregulation in Myotonic Dystrophy and Its Correction by Antisense Conjugates Targeting Disease-Causing Mutations [mRNA-seq]
| PRJNA1090497 | ENA
Project description:Myotonic dystrophy type 1 (DM1) is an incurable neuromuscular disorder caused by an expanded CTG repeat that is transcribed into r(CUG)exp. The RNA repeat expansion sequesters regulatory proteins such as Muscleblind-like protein 1 (MBNL1), which causes pre-mRNA splicing defects. The disease-causing r(CUG)exp has been targeted by antisense oligonucleotides, CRISPR-based approaches, and RNA-targeting small molecules. Herein, we describe a designer small molecule, Cugamycin, that targets the structure of r(CUG)exp and cleaves it in cells and in vivo. Cugamycin selectively cleaves r(CUG)exp while leaving short repeats of r(CUG) untouched. In contrast, oligonucleotides that recognize r(CUG) sequence rather than structure cleave both long and short r(CUG)-containing transcripts. In the HSALR mouse model of DM1, Cugamycin selectively ablates r(CUG)exp in disease-affected muscle. Transcriptomic, histological, and phenotypic studies demonstrate that Cugamycin broadly and specifically relieves DM1-associated defects without detectable off-targets. Thus, small molecules that bind and cleave RNA may have utility as lead chemical probes and medicines.
2019-03-22 | GSE127809 | GEO
Project description:This study examined the effects of antisense oligonucleotides (ASOs) on the muscle transcriptome in a transgenic mouse model of myotonic dystrophy. Two ASOs were tested in HSALR transgenic mice. Both of the ASOs targeted mRNA from a human skeletal actin (hACTA1) transgene. This transgene contains an expanded CTG repeat in the 3’ untranslated region (UTR) (Mankodi et al “Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat” Science 2000; 289:1769-72). ASO 445235 targeted the hACTA1 transcript in the 3’ UTR, downstream from the expanded repeat. ASO 190401 targeted the hACTA1 transcript in the coding region. The HSALR mice received 4 weeks of biweekly subcutaneous injections of vehicle (saline), ASO 190401, or ASO 445236 (n = 4 per group), at a dose of 25 mg/kg per injection. Wild-type mice of the same strain background received saline injections (n = 4). One week after the final injection, quadriceps muscle was harvested for RNA analysis.
2012-06-28 | GSE38962 | GEO
Project description:This study examined the effects of antisense oligonucleotides (ASOs) on the muscle transcriptome in a transgenic mouse model of myotonic dystrophy. Two ASOs were tested in HSALR transgenic mice. Both of the ASOs targeted mRNA from a human skeletal actin (hACTA1) transgene. This transgene contains an expanded CTG repeat in the 3M-bM-^@M-^Y untranslated region (UTR) (Mankodi et al M-bM-^@M-^\Myotonic dystrophy in transgenic mice expressing an expanded CUG repeatM-bM-^@M-^] Science 2000; 289:1769-72). ASO 445235 targeted the hACTA1 transcript in the 3M-bM-^@M-^Y UTR, downstream from the expanded repeat. ASO 190401 targeted the hACTA1 transcript in the coding region. The HSALR mice received 4 weeks of biweekly subcutaneous injections of vehicle (saline), ASO 190401, or ASO 445236 (n = 4 per group), at a dose of 25 mg/kg per injection. Wild-type mice of the same strain background received saline injections (n = 4). One week after the final injection, quadriceps muscle was harvested for RNA analysis. Four conditions, four arrays per condition, to compare WT and HSALR trangenic mice without treatment (saline) and to examine the effect of two oligos (vs. saline) in the HSALR transgenic mice.
2012-06-27 | E-GEOD-38962 | biostudies-arrayexpress
Project description:Compound loss of muscleblind-like function in myotonic dystrophy
| PRJNA207816 | ENA
Project description:Misregulated alternative splicing appears to be a major factor in the pathogenesis of myotonic dystrophy. The present study was done to further explore alternative splicing in this condition by doing exon-level analysis of mRNA from skeletal muscle of 8 subjects with type 1 myotonic dystrophy, 7 subjects with type 2 myotonic dystrophy, 8 disease controls (subjects with facioscapulohumeral muscular dystrophy), and 8 healthy controls . The ratios of signals from the various exons of a gene provided an index of altered exon inclusion/exclusion that was independent of the overall expression of that gene. There were numerous transcripts for which there was evidence of abnormal alternative splicing in subjects with myotonic dystrophy. For many of these transcripts, the abnormal splicing was confirmed by an independent RT-PCR approach. 31 subjects, one sample per subject, four groups: healthy subjects (n = 8), facioscapulohumeral dystrophy (n = 8), type 1 myotonic dystrophy (n = 8), type 2 myotonic dystrophy (n = 7)
2013-06-15 | E-GEOD-47968 | biostudies-arrayexpress
Project description: Not available
| S-EPMC8784167 | biostudies-literature