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Dnm2 downregulation by antisense oligonucleotide (ASO1) injections rescue a murine model of autosomal dominant centronuclear myopathy (Dnm2SL/+)

ABSTRACT: Dnm2 downregulation by antisense oligonucleotide (ASO1) injections rescue a murine model of autosomal dominant centronuclear myopathy (Dnm2SL/+)

PROVIDER: PRJNA671743 | ENA |

REPOSITORIES: ENA

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Dnm2 downregulation by antisense oligonucleotide (ASO1) injections rescue a murine model of autosomal dominant centronuclear myopathy (Dnm2SL/+)

Project description:In this study, we performed RNA sequencing on tibialis anterior muscle of male mice. WT (injected with ASO control) and Dnm2SL/+ (injected with ASO control) mice as well as ASO1 injected Dnm2SL/+ mice and ASO1 injected WT mice were sequenced at 7w of age. ASO1 targets specifically Dnm2 ARN.

2020-12-15 | GSE160078 | GEO

Dnm2 downregulation by antisense oligonucleotide (ASO1) injections rescue a murine model of recessive centronuclear myopathy (Bin1mck-/-)

Project description:Dnm2 downregulation by antisense oligonucleotide (ASO1) injections rescue a murine model of recessive centronuclear myopathy (Bin1mck-/-)

| PRJNA671741 | ENA

Dnm2 downregulation by antisense oligonucleotide (ASO1) injections rescue a murine model of recessive centronuclear myopathy (Bin1mck-/-)

Project description:In this study, we performed RNA sequencing on tibialis anterior muscle of male mice. WT (injected with PBS) and Bin1mck-/- (injected with PBS) mice as well as ASO1 injected Bin1mck-/- mice and ASO1 injected WT mice were sequenced at 7 weeks of age. ASO1 targets specifically Dnm2 ARN.

2020-12-15 | GSE160077 | GEO

Antisense oligonucleotide-mediated Dnm2 knockdown prevents and reverts myotubular myopathy in mice.

Project description:Centronuclear myopathies (CNM) are non-dystrophic muscle diseases for which no effective therapy is currently available. The most severe form, X-linked CNM, is caused by myotubularin 1 (MTM1) loss-of-function mutations, while the main autosomal dominant form is due to dynamin2 (DNM2) mutations. We previously showed that genetic reduction of DNM2 expression in Mtm1 knockout (Mtm1KO) mice prevents development of muscle pathology. Here we show that systemic delivery of Dnm2 antisense oligonucleotides (ASOs) into Mtm1KO mice efficiently reduces DNM2 protein level in muscle and prevents the myopathy from developing. Moreover, systemic ASO injection into severely affected mice leads to reversal of muscle pathology within 2 weeks. Thus, ASO-mediated DNM2 knockdown can efficiently correct muscle defects due to loss of MTM1, providing an attractive therapeutic strategy for this disease.

| S-EPMC5467247 | biostudies-literature

Genetic downregulation of Dnm2 as a therapeutic approach in a murine model of X-linked myotubular myopathy (Mtm1-/y)

Project description:In this study, we performed RNA sequencing on tibialis anterior muscle of male mice. WT and Mtm1 deficient (Mtm1-/y) mice as well as on Dnm2+/- mice and on Mtm1-/y mice crossed with Dnm2+/- (Mtm1-/yDnm2+/-) were sequenced. A longitudinal follow up was established by sequencing all the genotypes at E18.5, 2w and 7w.

2020-12-15 | GSE160079 | GEO

Genetic downregulation of Dnm2 as a therapeutic approach in a murine model of X-linked myotubular myopathy (Mtm1-/y)

Project description:In this study, we performed mass spectometry on tibialis anterior muscle of male mice. WT and Mtm1 deficient (Mtm1-/y) mice as well as on Dnm2+/- mice and on Mtm1-/y mice crossed with Dnm2+/- (Mtm1-/yDnm2+/-) were analyzed. A longitudinal follow up was established by analyzing all the genotypes at E18.5, 2w and 7w.

2022-10-13 | PXD021725 | Pride

Reducing dynamin 2 (DNM2) rescues DNM2-related dominant centronuclear myopathy.

Project description:Centronuclear myopathies (CNM) are a group of severe muscle diseases for which no effective therapy is currently available. We have previously shown that reduction of the large GTPase DNM2 in a mouse model of the X-linked form, due to loss of myotubularin phosphatase MTM1, prevents the development of the skeletal muscle pathophysiology. As DNM2 is mutated in autosomal dominant forms, here we tested whether DNM2 reduction can rescue DNM2-related CNM in a knock-in mouse harboring the p.R465W mutation (Dnm2 RW/+) and displaying a mild CNM phenotype similar to patients with the same mutation. A single intramuscular injection of adeno-associated virus-shRNA targeting Dnm2 resulted in reduction in protein levels 5 wk post injection, with a corresponding improvement in muscle mass and fiber size distribution, as well as an improvement in histopathological CNM features. To establish a systemic treatment, weekly i.p. injections of antisense oligonucleotides targeting Dnm2 were administered to Dnm2 RW/+mice for 5 wk. While muscle mass, histopathology, and muscle ultrastructure were perturbed in Dnm2 RW/+mice compared with wild-type mice, these features were indistinguishable from wild-type mice after reducing DNM2. Therefore, DNM2 knockdown via two different strategies can efficiently correct the myopathy due to DNM2 mutations, and it provides a common therapeutic strategy for several forms of centronuclear myopathy. Furthermore, we provide an example of treating a dominant disease by targeting both alleles, suggesting that this strategy may be applied to other dominant diseases.

| S-EPMC6205463 | biostudies-literature

RNA sequencing of control and dnm2-knockout mouse sciatic nerves

Project description:In this study, we analyzed the transcriptome profiles of mouse sciatic nerves after developmental (P1 and P5) or inducible (4 weeks post Tamoxifen) deletion of Dnm2 conditionally in Schwann cells (using a P0Cre-driven or a P0CreERT2-driven recombination of floxed alleles, respectively) as compared to controls (floxed Dnm2 homozygous, Cre-negative).

2019-01-16 | GSE113106 | GEO

The FSHD effector protein Dux promotes myopathy via Myostatin-Smad signaling

Project description:Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant condition that is characterised by a progressive degeneration and weakness of skeletal muscle fibers. The underlying cause of FSHD has been attributed to inappropriate expression of the transcription factor double homeobox (Dux); however, the mechanisms leading to myopathy in response to Dux expression remain incompletely understood. To study the acute effects of Dux activation in mammalian skeletal muscle fibers, we generated a recombinant adeno-associated viral vector allowing tunable Dux expression. Consistent with previous findings, we confirmed that the ectopic expression of Dux in mouse skeletal muscle results in a degenerative myopathy. Building on these findings, we observed that the acute expression of Dux in muscle fibers causes profound transcriptome changes prior to the onset of pathology. Furthermore, muscles expressing Dux display elevated levels of the TGF-beta superfamily member, Myostatin and increased Smad2/3 activity. Notably, inhibition of Myostatin is sufficient to prevent Dux-induced myopathy. Collectively, these findings support further investigation of interventions targeting the Myostatin-Smad2/3 pathway as prospective approaches to treating myopathy associated with Dux mis-expression.

2021-12-31 | GSE108828 | GEO

Transcriptomic analysis of the soleus muscle extracted from Dnm2 K562E point-mutant heterozygous mice

Project description:RNA sequencing was performed to evaluate the impact of Dnm2 K562E mutation in the soleus muscle. The assessment of the dataset reveals a large number of differentially regulated transcripts between animals of both genotypes. This is consistent with a dominant phenotype caused by the Dnm2 K562E point mutation on the muscle.

2020-02-24 | GSE134488 | GEO

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