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Gene therapy prolongs survival and restores function in murine and canine models of myotubular myopathy.

ABSTRACT: Loss-of-function mutations in the myotubularin gene (MTM1) cause X-linked myotubular myopathy (XLMTM), a fatal, congenital pediatric disease that affects the entire skeletal musculature. Systemic administration of a single dose of a recombinant serotype 8 adeno-associated virus (AAV8) vector expressing murine myotubularin to Mtm1-deficient knockout mice at the onset or at late stages of the disease resulted in robust improvement in motor activity and contractile force, corrected muscle pathology, and prolonged survival throughout a 6-month study. Similarly, single-dose intravascular delivery of a canine AAV8-MTM1 vector in XLMTM dogs markedly improved severe muscle weakness and respiratory impairment, and prolonged life span to more than 1 year in the absence of toxicity or a humoral or cell-mediated immune response. These results demonstrate the therapeutic efficacy of AAV-mediated gene therapy for myotubular myopathy in small- and large-animal models, and provide proof of concept for future clinical trials in XLMTM patients.

SUBMITTER: Childers MK

PROVIDER: S-EPMC4105197 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Gene therapy prolongs survival and restores function in murine and canine models of myotubular myopathy.

Childers Martin K MK Joubert Romain R Poulard Karine K Moal Christelle C Grange Robert W RW Doering Jonathan A JA Lawlor Michael W MW Rider Branden E BE Jamet Thibaud T Danièle Nathalie N Martin Samia S Rivière Christel C Soker Thomas T Hammer Caroline C Van Wittenberghe Laetitia L Lockard Mandy M Guan Xuan X Goddard Melissa M Mitchell Erin E Barber Jane J Williams J Koudy JK Mack David L DL Furth Mark E ME Vignaud Alban A Masurier Carole C Mavilio Fulvio F Moullier Philippe P Beggs Alan H AH Buj-Bello Anna A

Science translational medicine 20140101 220

Loss-of-function mutations in the myotubularin gene (MTM1) cause X-linked myotubular myopathy (XLMTM), a fatal, congenital pediatric disease that affects the entire skeletal musculature. Systemic administration of a single dose of a recombinant serotype 8 adeno-associated virus (AAV8) vector expressing murine myotubularin to Mtm1-deficient knockout mice at the onset or at late stages of the disease resulted in robust improvement in motor activity and contractile force, corrected muscle pathology ...[more]

PMID: 24452262

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Project description:Purpose: The goal of this study was to investigate the transcriptional profile of genes expressed in the quadriceps muscle of myotubularin deficient (Mtm1-/-) mice, and determine whether improvements in the pathophysiology of tamoxifen treated Mtm1-/- mice are a consequence of ER-dependent transcriptional modulation. Methods: Muscle mRNA profiles from quadriceps of 36-day-old wild-type (WT), myotubularin deficient (Mtm1-/-) mice, and tamoxifen treated WT and Mtm1-/- mice were generated by deep sequencing, in triplicate or quadruplicate, using Illumina HiSeq 2500. Read sets from each of the 14 samples across the four conditions were aligned to the reference genome (GRCm38/MM10 version of the Mus musculus genome) and transcriptome using STAR (Dobin et al. Bioinformatics 2013 PMID: 23104886) two-step alignment to generate a Binary Alignment Map file (BAM file). Coordinate sorted BAM files were used to quantify transcript abundance (count data) using HTSeq (Anders et al. Bioinformatics 2014, PMID: 25260700). Raw read counts generated were used as input for differential gene expression analysis, carried out using both DESeq (Anders and Huber 2010) and edgeR (Robinson, McCarthy, and Smyth 2010) R/Bioconductor packages. This was carried out in a pair-wise manner between any two conditions that were considered. FDR adjusted p-values from both edgeR and DESeq was used to determine genes that are significantly differentially expressed between the conditions tested. Finally, we used the GoSeq R/Bioconductor package (Young MD, et al Genome Biology, 11, pp. R14) to identify pathways that were significantly enriched for differentially expressed genes between any two conditions. Results: Using an established data analysis workflow, 65 million reads were aligned per sample (>90% exonic). We observed 849 differentially expressed transcripts in untreated mtm1-/-mice (p< 0.01) in comparison to wild-type (WT) controls. Furthermore, we identified 29 differentially expressed genes (p<0.01) between mtm1-/- mice and their TAM-treated mtm1-/- mice. In particular, we observed that the transcriptional profiles of mtm1 -/- mice and tamoxifen-treated mtm1-/- mice cluster together and are distinct from wild-type contros. Moreover, no significant changes were observed in the expression of estrogen-response genes that are known gene targets of tamoxifen; no significant transcriptional changes were observed in well-known MTM-related genes.This strongly indicates that, contrary to its well-established function as a transcriptional modulator, tamoxifen improves the pathophysiology of myotubular myopathy in a post-transcriptional manner. Concusions: Our study represents the first comprehensive analysis of the whole transcriptome of the Mtm1-/- and tamoxifen treated Mtm1-/- mouse, generated by RNA-seq technology. The data reported here provides a framework a comparative investigation of the expression profiles in Mtm1-/- mice and tamoxifen treated Mtm1-/- mice. Importantly, our results demonstrate that in our MTM murine model, tamoxifen does not appear to alter the transcriptional profile of many estrogen-receptor (ER) related genes, and moreover does not appear to alter the transcriptional profile of genes that are abnormally expressed in Mtm1-/- mice alone. This suggests that tamoxifen is acting to improve the pathophysiology of the MTM mouse model in a transcriptionally-indepedent manner.

Project description:Centronuclear myopathy (CNM) is an inherited neuromuscular disorder characterised by clinical features of a congenital myopathy and centrally placed nuclei on muscle biopsy.The incidence of X-linked myotubular myopathy is estimated at 2/100000 male births but epidemiological data for other forms are not currently available.The clinical picture is highly variable. The X-linked form usually gives rise to a severe phenotype in males presenting at birth with marked weakness and hypotonia, external ophthalmoplegia and respiratory failure. Signs of antenatal onset comprise reduced foetal movements, polyhydramnios and thinning of the ribs on chest radiographs; birth asphyxia may be the present. Affected infants are often macrosomic, with length above the 90th centile and large head circumference. Testes are frequently undescended. Both autosomal-recessive (AR) and autosomal-dominant (AD) forms differ from the X-linked form regarding age at onset, severity, clinical characteristics and prognosis. In general, AD forms have a later onset and milder course than the X-linked form, and the AR form is intermediate in both respects.Mutations in the myotubularin (MTM1) gene on chromosome Xq28 have been identified in the majority of patients with the X-linked recessive form, whilst AD and AR forms have been associated with mutations in the dynamin 2 (DNM2) gene on chromosome 19p13.2 and the amphiphysin 2 (BIN1) gene on chromosome 2q14, respectively. Single cases with features of CNM have been associated with mutations in the skeletal muscle ryanodine receptor (RYR1) and the hJUMPY (MTMR14) genes.Diagnosis is based on typical histopathological findings on muscle biopsy in combination with suggestive clinical features; muscle magnetic resonance imaging may complement clinical assessment and inform genetic testing in cases with equivocal features. Genetic counselling should be offered to all patients and families in whom a diagnosis of CNM has been made.The main differential diagnoses include congenital myotonic dystrophy and other conditions with severe neonatal hypotonia.Management of CNM is mainly supportive, based on a multidisciplinary approach. Whereas the X-linked form due to MTM1 mutations is often fatal in infancy, dominant forms due to DNM2 mutations and some cases of the recessive BIN1-related form appear to be associated with an overall more favourable prognosis.

Dataset Information

Gene therapy prolongs survival and restores function in murine and canine models of myotubular myopathy.

Publications

Gene therapy prolongs survival and restores function in murine and canine models of myotubular myopathy.

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