A5085648387- Muscle Physiology and Disorders
- Cellular transport and secretion
- Genetic Neurodegenerative Diseases
- Neurogenetic and Muscular Disorders Research
- Cardiomyopathy and Myosin Studies
- Ubiquitin and proteasome pathways
- CRISPR and Genetic Engineering
- Virus-based gene therapy research
- RNA modifications and cancer
- Metabolism, Diabetes, and Cancer
- Mitochondrial Function and Pathology
- Genetics and Neurodevelopmental Disorders
- RNA Research and Splicing
- Neurological disorders and treatments
- Ion channel regulation and function
- Nuclear Structure and Function
- Calcium signaling and nucleotide metabolism
- RNA regulation and disease
- Lysosomal Storage Disorders Research
- Cancer-related molecular mechanisms research
- CAR-T cell therapy research
- Carbohydrate Chemistry and Synthesis
- Genomics and Rare Diseases
- Statistical Methods in Clinical Trials
- Congenital heart defects research
Genethon (France)
2015-2024
Inserm
2002-2024
Université Paris-Saclay
2017-2024
Université d'Évry Val-d'Essonne
2018-2023
Integrated Genetic Approaches in Therapeutic Discovery for Rare Diseases
2018
École Pratique des Hautes Études
2017
Boston Children's Hospital
2015
Institut de génétique et de biologie moléculaire et cellulaire
2002-2008
Centre National de la Recherche Scientifique
2002
BackgroundX-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which caused by mutations MTM1. No therapies are approved for this disease. We aimed to assess the safety and efficacy of resamirigene bilparvovec, an adeno-associated viral vector serotype 8 delivering human MTM1.MethodsASPIRO open-label, dose-escalation trial at seven academic medical centres Canada, France, Germany, USA. included boys younger than 5 years with X-linked...
Abstract Muscular dystrophies are characterized by weakness and wasting of skeletal muscle tissues. Several drugs targeting the myostatin pathway have been used in clinical trials to increase mass function but most showed limited efficacy. Here we show that expression components signaling is downregulated or atrophying diseases, with a decrease activin receptor, an antagonist, follistatin. We also provide vivo evidence congenital myotubular myopathy mouse model (knock-out for myotubularin...
X-linked myotubular myopathy (XLMTM) results from MTM1 gene mutations and myotubularin deficiency. Most XLMTM patients develop severe muscle weakness leading to respiratory failure death, typically within 2 years of age. Our objective was evaluate the efficacy safety systemic therapy in p.N155K canine model by performing a dose escalation study. A recombinant adeno-associated virus serotype 8 (rAAV8) vector expressing (cMTM1) under muscle-specific desmin promoter (rAAV8-cMTM1) administered...
Bioengineering of viral vectors for therapeutic gene delivery is a pivotal strategy to reduce doses, facilitate manufacturing, and improve efficacy patient safety. Here, we engineered myotropic adeno-associated (AAV) via semirational, combinatorial approach that merges AAV capsid peptide library screens. We first identified shuffled AAVs with increased specificity in the murine skeletal muscle, diaphragm, heart, concurrent liver detargeting. Next, boosted muscle by displaying on surface. In...
Myotonic dystrophy type 1 (DM1) is caused by a CTG repeat expansion located in the 3′ UTR of DMPK gene. Expanded transcripts aggregate into nuclear foci and alter function RNA-binding proteins, leading to defects alternative splicing numerous pre-mRNAs. To date, there no curative treatment for DM1. Here we investigated gene-editing strategy using CRISPR-Cas9 system from Staphylococcus aureus (Sa) delete repeats human locus. Co-expression SaCas9 selected pairs single-guide RNAs (sgRNAs)...
Spinal muscular atrophy (SMA) is an autosomal recessive disease of variable severity caused by mutations in the SMN1 gene. Deficiency ubiquitous SMN function results spinal cord α-motor neuron degeneration and proximal muscle weakness. Gene replacement therapy with recombinant adeno-associated viral (AAV) vectors showed therapeutic efficacy several animal models SMA. Here, we report a study aimed at analyzing biodistribution serotype-9, self-complementary AAV vector expressing...
Significance Myotubular myopathy is a fatal muscle disease due to deficiency in phosphoinositide 3-phosphatase called myotubularin. We identify critical alterations involved the pathophysiology of disease, and we reveal beneficial effect pharmacological treatment. Specifically, demonstrate that disease-associated dysfunction Ca 2+ signaling strongly heterogeneous at subcellular level, affects amplitude activation kinetics sarcoplasmic reticulum release, promotes -gated opening mode calcium...
Multiple clinical trials employing recombinant adeno-associated viral (rAAV) vectors have been initiated for neuromuscular disorders, including Duchenne and limb-girdle muscular dystrophies, spinal atrophy, recently X-linked myotubular myopathy (XLMTM). Our previous work on a canine model of XLMTM showed that single rAAV8-cMTM1 systemic infusion corrected structural abnormalities within the muscle restored contractile function, with affected dogs surviving more than 4 years post injection....
X-linked myotubular myopathy (XLMTM) is a severe congenital disorder in male infants that leads to generalized skeletal muscle weakness and frequently associated with fatal respiratory failure. XLMTM caused by loss-of-function mutations the MTM1 gene, which encodes myotubularin, founder member of family 15 homologous proteins mammals. We recently demonstrated therapeutic efficacy intravenous delivery rAAV vectors expressing animal models myopathy. Here, we tested whether closest homologues...
ASPIRO is an ongoing, open-label, randomized study (NCT03199469) evaluating safety/efficacy of AT132, investigational gene therapy for delivery functional MTM1 copies.
We previously reported in Science Translational Medicine ( STM ) unprecedented results (1) from gene replacement experiments MTM1 -mutant animal models of X-linked myotubular myopathy (XLMTM, OMIM 310400) (2). This devastating congenital muscle disorder deficiency myotubularin, a phosphatidylinositol-3-phosphatase required for skeletal function, growth and ultrastructural organization (3-6). The overall median survival XLMTM patients is only 29 months (7) the majority who survive beyond two...
Abstract In mammalian skeletal muscle, the propagation of surface membrane depolarization into interior muscle fibre along transverse (T) tubular network is essential for synchronized release calcium from sarcoplasmic reticulum (SR) via ryanodine receptors (RyRs) in response to conformational change voltage‐sensor dihydropyridine receptors. Deficiency 3‐phosphoinositide phosphatase myotubularin (MTM1) has been reported disrupt T‐tubules, resulting impaired SR release. Here confocal...
Myotonic dystrophy type 1 (DM1) belongs to the group of nucleotide repeat disorders. More specifically this autosomal form muscular is caused by expansion CTG trinucleotide located at 3' untranslated region (3'-UTR) DMPK gene. Elongated CUG repeats mutated mRNAs become sequestration sites for splicing factors, and induce formation stable ribonucleoprotein complexes visualized as foci. As a consequence, alternative numerous transcripts dysregulated, which leads DM1 pathological alterations...
Neuromuscular junctions (NMJs) are highly specialized synapses between lower motor neurons and skeletal muscle fibers that play an essential role in the transmission of molecules from nervous system to voluntary muscles, leading contraction. They affected many human diseases, including inherited neuromuscular disorders such as Duchenne muscular dystrophy (DMD), congenital myasthenic syndromes (CMS), spinal atrophy (SMA), amyotrophic lateral sclerosis (ALS). Therefore, monitoring morphology...