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Promising AAV.U7snRNAs vectors targeting DMPK improve DM1 hallmarks in patient-derived cell lines

ABSTRACT: Promising AAV.U7snRNAs vectors targeting DMPK improve DM1 hallmarks in patient-derived cell lines

PROVIDER: PRJNA978624 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24799156_1.fastq.gz	Fastqsanger.gz
	SRR24799156_2.fastq.gz	Fastqsanger.gz
	SRR24799157_1.fastq.gz	Fastqsanger.gz
	SRR24799157_2.fastq.gz	Fastqsanger.gz
	SRR24799158_1.fastq.gz	Fastqsanger.gz

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Promising AAV.U7snRNAs vectors targeting <i>DMPK</i> improve DM1 hallmarks in patient-derived cell lines.

Project description:Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults and affects mainly the skeletal muscle, heart, and brain. DM1 is caused by a CTG repeat expansion in the 3'UTR region of the DMPK gene that sequesters muscleblind-like proteins, blocking their splicing activity and forming nuclear RNA foci. Consequently, many genes have their splicing reversed to a fetal pattern. There is no treatment for DM1, but several approaches have been explored, including antisense oligonucleotides (ASOs) aiming to knock down DMPK expression or bind to the CTGs expansion. ASOs were shown to reduce RNA foci and restore the splicing pattern. However, ASOs have several limitations and although being safe treated DM1 patients did not demonstrate improvement in a human clinical trial. AAV-based gene therapies have the potential to overcome such limitations, providing longer and more stable expression of antisense sequences. In the present study, we designed different antisense sequences targeting exons 5 or 8 of DMPK and the CTG repeat tract aiming to knock down DMPK expression or promote steric hindrance, respectively. The antisense sequences were inserted in U7snRNAs, which were then vectorized in AAV8 particles. Patient-derived myoblasts treated with AAV8. U7snRNAs showed a significant reduction in the number of RNA foci and re-localization of muscle-blind protein. RNA-seq analysis revealed a global splicing correction in different patient-cell lines, without alteration in DMPK expression.

| S-EPMC10309041 | biostudies-literature

Promising AAV.U7snRNAs vectors targeting DMPK improve DM1 hallmarks in patient-derived cell lines

Project description:To evaluate the effect of AAV.U7snRNAs in the gene expression and alternative expression profiles of myotonic dystrophy cell lines.

2023-06-08 | GSE233947 | GEO

Long-read sequencing for the assessment of therapeutic CRISPR/Cas9 strategy for the removal of aberrant DM1-causing CTG repeats in DMPK gene locus

Project description:The genetic cause of Myotonic Dystrophy Type 1 (DM1) is the expansion of unstable CTG-repeats in the 3´ untranslated region of the DMPK gene. Therapeutic gene editing for treatment of monogenic diseases could in principle remove definitively the disease-causing genetic defect. Here we describe the application of the CRISPR/Cas9 strategy to remove the CTG-expansion in the DMPK gene in myogenic cells derived from a DM1 patient that is heterozygous for the expansion. The efficacy of on-target genomic events was assessed by performing long-read DNA sequencing (Oxford Nanopore Technologies) after applying Cas9-mediated target enrichment of the Regions Of Interest (ROI), enabling the simultaneous analysis (a) of cuts by both sgRNAs resulting in the effective excision of the CTG expansion, (b) of cuts induced only by a single sgRNA, (c) of the potential occurrence of aberrant events such as inversions, and (d) the existence of non-edited sequences, within the same sample.

2025-02-26 | GSE279054 | GEO

Bisulfite-seq: Analysis of CpG methylation at two CTCF binding sites flanking the CTG repeats of DMPK.

Project description:Bisulfite sequencing was performed on GM04604 (UN-B), GM06077 (DM1-A), and GM04648 (DM1-B) patient cells to determine the levels of CpG methylation present at two CTCF sites closely flanking the CTG repeats of DMPK.

2020-04-07 | GSE148177 | GEO

Dmpk

Project description:Rattus norvegicus Dmpk, DM1 protein kinase [Source:RGD Symbol;Acc:1309825], is expressed in 4 baseline experiment(s);

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Dmpk

Project description:Rattus norvegicus Dmpk, DM1 protein kinase [Source:RGD Symbol;Acc:1309825], is differentially expressed in 33 experiment(s);

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DMPK

Project description:Homo sapiens DMPK, DM1 protein kinase [Source:HGNC Symbol;Acc:HGNC:2933], is expressed in 46 baseline experiment(s);

| ENSG00000104936 | ExpressionAtlas

DMPK

Project description:Homo sapiens DMPK, DM1 protein kinase [Source:HGNC Symbol;Acc:HGNC:2933], is differentially expressed in 147 experiment(s);

| ENSG00000104936 | ExpressionAtlas

Myotonic dystrophy type 1 (DM1) leads to altered mRNA expression in heart tissue

Project description:Myotonic dystrophy type 1 (DM1) is a dominantly inherited disease that affects multiple organ systems. Cardiac dysfunction is the second leading cause of death in DM1. We quantified gene expression in heart tissue from a heart-specific DM1 mouse model (EpA960/MCM) which inducibly expresses human DMPK exon 15 containing 960 CUG expanded repeats and that reproduced Celf1 up regulation. To assess if, in addition to splicing and miRNA defects, CUGexp RNA also perturbed the steady state mRNA levels of genes, we carried out a microarray study on wildtype E14, adult, MCM controls and DM1 mouse hearts. As anticipated we noted a large number of genes to be developmentally regulated in wildtype hearts, however, within 72h of induction of CUGexp RNA there appeared to be a coordinate adult-to-embryonic shift in steady state levels of many genes. We identified transcripts over-expressed or under-expressed in hearts of wildtype adult mice, wildtype embryonic day 14 (E14), and DM1 mice induced to express CUGexp RNA for 72h and 1wk, when compared to MCM controls. Multiple group comparison.

2014-01-24 | E-GEOD-48991 | biostudies-arrayexpress

DMPK

Project description:Macaca mulatta DMPK, DM1 protein kinase [Source:NCBI gene (formerly Entrezgene);Acc:715328], is differentially expressed in 1 experiment(s);

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