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AV8 gene therapy and environmental exposure precipitate cholestatic liver disease in a mouse model of X-linked myotubular myopathy

ABSTRACT: AV8 gene therapy and environmental exposure precipitate cholestatic liver disease in a mouse model of X-linked myotubular myopathy

PROVIDER: PRJNA1101466 | ENA |

REPOSITORIES: ENA

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	SRR28720701_1.fastq.gz	Fastqsanger.gz
	SRR28720701_2.fastq.gz	Fastqsanger.gz
	SRR28720702_1.fastq.gz	Fastqsanger.gz
	SRR28720702_2.fastq.gz	Fastqsanger.gz

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Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy

Project description:Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy

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AV8 gene therapy and environmental exposure precipitate cholestatic liver disease in a mouse model of X-linked myotubular myopathy

Project description:AAV-associated hepatotoxicity has been observed in patients, with poor concordance between preclinical studies and clinical outcomes. Gene therapy for X-linked myotubular myopathy (XLMTM) has epitomized this therapeutic dilemma, as an AAV8-MTM1 clinical trial has shown efficacy but also fatal liver failure in a subset of individuals. In the present study, we address this conundrum, and demonstrate for the first time in mice that early-life nutrition and AAV exposure can promote liver injury. Specifically, XLMTM mice fed a purified-diet manifest liver dysfunction that mirrors what is seen in patients. AAV8-therapy increases this susceptibility, and additionally promotes liver injury in wild-type mice. Notably, non-viral lipid nanoparticle delivery of MTM1 rescues the XLMTM liver phenotype, offering a potential treatment strategy to mitigate liver consequences in patients. Together, these data provide critical insight into the adverse events seen in viral-gene therapy studies and set the stage for defining their pathomechanisms and identifying potential therapies.

2025-06-01 | GSE264209 | GEO

Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy

Project description:X-linked myotubular myopathy (XLMTM) is a fatal congenital disorder caused by mutations in the MTM1 gene. Currently, there are no approved treatments, though AAV8-mediated gene transfer therapy has shown promise in animal models and preliminarily in patients. However, four patients with XLMTM treated with gene therapy have died from progressive liver failure, and hepatobiliary disease has now been recognized more broadly in association with XLMTM. In an attempt to understand whether loss of MTM1 itself is associated with liver pathology, we have characterized a novel liver phenotype in a zebrafish model of this disease. Specifically, we have found that loss-of-function mutations in mtm1 lead to severe liver abnormalities including impaired bile flux, structural abnormalities of the bile canaliculus, and improper endosomal-mediated trafficking of canalicular transporters. Using a reporter tagged Mtm1 zebrafish line, we have established localization of Mtm1 in the liver in association with Rab11 and canalicular transport proteins, and demonstrated that hepatocyte specific re-expression of Mtm1 can rescue the cholestatic phenotype. Lastly, we completed a targeted chemical screen, and found that Dynasore, a dynamin II inhibitor, is able to partially restore bile flow and transporter localization to the canalicular membrane. In summary, we demonstrate for the first time liver abnormalities that are directly caused by MTM1 mutation in a pre-clinical model, thus establishing the critical framework for better understanding and comprehensive treatment of the human disease.

2023-08-10 | GSE235571 | GEO

X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition

Project description:X-linked myotubular myopathy (XLMTM) is a fatal neuromuscular disorder caused by loss of function mutations in MTM1 . At present, there are no directed therapies for XLMTM, and incomplete understanding of disease pathomechanisms. To address these knowledge gaps, we performed a drug screen in mtm1 mutant zebrafish andidentified four positive hits, including valproic acid, which functions as a potent suppressor of the mtm1 zebrafish phenotype via HDAC inhibition. We translated these findings to a mouse XLMTM model, and showed that valproic acid ameliorates the murine phenotype.

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Natural history of a mouse model of X-linked myotubular myopathy

Project description:Natural history of a mouse model of X-linked myotubular myopathy

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Natural history of a mouse model of X-linked myotubular myopathy

Project description:X-linked myotubular myopathy (XLMTM) is a severe monogenetic disorder of the skeletal muscle. It is caused by loss-of-expression/function mutations in the myotubularin (MTM1) gene. Much of what is known about the disease, as well as the treatment strategies, has been uncovered through experimentation in pre-clinical models, particularly the Mtm1 gene knockout mouse line (Mtm1 KO). Despite this understanding, and the identification of potential therapies, much remains to be understood about XLMTM disease pathomechanisms, and about the normal functions of MTM1 in muscle development. To lay the groundwork for addressing these knowledge gaps, we performed a natural history study of Mtm1 KO mice. This included longitudinal comparative analyses of motor phenotype, transcriptome and proteome profiles, muscle structure and targeted molecular pathways.We identified age-associated changes in gene expression, mitochondrial function, myofiber size and key molecular markers, including DNM2. Importantly, some molecular and histopathologic changes preceded overt phenotypic changes, while others, such as triad structural alternations, occurred coincidentally with the presence of severe weakness. In total, this study provides a comprehensive longitudinal evaluation of the murine XLMTM disease process, and thus provides a critical framework for future investigations.

2022-07-08 | GSE207447 | GEO

X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition

Project description:X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition

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Compensatory mechanisms in non-muscle organs in myotubular myopathy

Project description:Compensatory mechanisms in non-muscle organs in myotubular myopathy

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Compensatory mechanisms in non-muscle organs in myotubular myopathy

Project description:X-Linked myotubular myopathy (XLMTM), is associated with very severe muscle weakness and reduced life expectancy. Liver dysfunction was also reported. The pathomechanism and the impact of non-muscular defects affecting survival are barely known. Here, we investigated organ-specific effects of XLMTM in the faithful Mtm1-/y mouse model. We performed RNA-sequencing to identify a shared mechanism in several skeletal muscles, and to investigate potential phenotypes and/or compensation in heart and liver. The cardiac and hepatic function and structural integrity were also studied in vivo and in vitro. There was no defect in liver function and morphology. A disease signature shared across several skeletal muscles including diaphragm highlighted dysregulations of muscle development, inflammation, cell adhesion and oxidative phosphorylation as main pathomechanisms. Heart displayed only slight functional alterations without obvious structural defects. An opposite dysregulation of specific pathways in cardiac compared to skeletal muscles was revealed at the transcriptome level. More specifically, biochemical and cellular experiments demonstrated that OXPHOS mitochondrial function, cell adhesion and beta integrin trafficking were strongly affected in skeletal muscle and normal in cardiac muscle. Moreover, biomarkers reflecting the molecular activity of MTM1, such as PtdIns3P and dynamin 2 levels, were increased in the skeletal muscles but not in cardiac muscle. Overall, these data identified a compensatory mechanism preserving cardiac function, indicating therapeutic targets to cure the severe skeletal muscle defects in XLMTM.

2024-12-18 | GSE242761 | GEO

Tamoxifen treatment as a therapeutic approach in a murine model of X-linked myotubular myopathy (Mtm1-/y)

Project description:Tamoxifen treatment as a therapeutic approach in a murine model of X-linked myotubular myopathy (Mtm1-/y)

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