15 results on '"Faouzi Zarrouki"'
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2. AAV-Mediated Restoration of Dystrophin-Dp71 in the Brain of Dp71-Null Mice: Molecular, Cellular and Behavioral Outcomes
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Ophélie Vacca, Faouzi Zarrouki, Charlotte Izabelle, Mehdi Belmaati Cherkaoui, Alvaro Rendon, Deniz Dalkara, and Cyrille Vaillend
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dystrophin-Dp71 ,glia ,AAV ,gene therapy ,behavior ,brain ,Cytology ,QH573-671 - Abstract
A deficiency in the shortest dystrophin-gene product, Dp71, is a pivotal aggravating factor for intellectual disabilities in Duchenne muscular dystrophy (DMD). Recent advances in preclinical research have achieved some success in compensating both muscle and brain dysfunctions associated with DMD, notably using exon skipping strategies. However, this has not been studied for distal mutations in the DMD gene leading to Dp71 loss. In this study, we aimed to restore brain Dp71 expression in the Dp71-null transgenic mouse using an adeno-associated virus (AAV) administrated either by intracardiac injections at P4 (ICP4) or by bilateral intracerebroventricular (ICV) injections in adults. ICP4 delivery of the AAV9-Dp71 vector enabled the expression of 2 to 14% of brain Dp71, while ICV delivery enabled the overexpression of Dp71 in the hippocampus and cortex of adult mice, with anecdotal expression in the cerebellum. The restoration of Dp71 was mostly located in the glial endfeet that surround capillaries, and it was associated with partial localization of Dp71-associated proteins, α1-syntrophin and AQP4 water channels, suggesting proper restoration of a scaffold of proteins involved in blood–brain barrier function and water homeostasis. However, this did not result in significant improvements in behavioral disturbances displayed by Dp71-null mice. The potential and limitations of this AAV-mediated strategy are discussed. This proof-of-concept study identifies key molecular markers to estimate the efficiencies of Dp71 rescue strategies and opens new avenues for enhancing gene therapy targeting cognitive disorders associated with a subgroup of severely affected DMD patients.
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- 2024
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3. CD38‐NADase is a new major contributor to Duchenne muscular dystrophic phenotype
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Antoine de Zélicourt, Abdallah Fayssoil, Mbarka Dakouane‐Giudicelli, Isley De Jesus, Ahmed Karoui, Faouzi Zarrouki, Florence Lefebvre, Arnaud Mansart, Jean‐Marie Launay, Jerome Piquereau, Mariana G Tarragó, Marcel Bonay, Anne Forand, Sophie Moog, France Piétri‐Rouxel, Elise Brisebard, Claudia C S Chini, Sonu Kashyap, Matthew J Fogarty, Gary C Sieck, Mathias Mericskay, Eduardo N Chini, Ana Maria Gomez, José‐Manuel Cancela, and Sabine de la Porte
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calcium ,cardiomyopathy ,CD38 ,DMD ,NAD+ ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration. Two important deleterious features are a Ca2+ dysregulation linked to Ca2+ influxes associated with ryanodine receptor hyperactivation, and a muscular nicotinamide adenine dinucleotide (NAD+) deficit. Here, we identified that deletion in mdx mice of CD38, a NAD+ glycohydrolase‐producing modulators of Ca2+ signaling, led to a fully restored heart function and structure, with skeletal muscle performance improvements, associated with a reduction in inflammation and senescence markers. Muscle NAD+ levels were also fully restored, while the levels of the two main products of CD38, nicotinamide and ADP‐ribose, were reduced, in heart, diaphragm, and limb. In cardiomyocytes from mdx/CD38−/− mice, the pathological spontaneous Ca2+ activity was reduced, as well as in myotubes from DMD patients treated with isatuximab (SARCLISA®) a monoclonal anti‐CD38 antibody. Finally, treatment of mdx and utrophin–dystrophin‐deficient (mdx/utr−/−) mice with CD38 inhibitors resulted in improved skeletal muscle performances. Thus, we demonstrate that CD38 actively contributes to DMD physiopathology. We propose that a selective anti‐CD38 therapeutic intervention could be highly relevant to develop for DMD patients.
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- 2022
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4. Long-Term Efficacy of AAV9-U7snRNA-Mediated Exon 51 Skipping in mdx52 Mice
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Philippine Aupy, Faouzi Zarrouki, Quentin Sandro, Cécile Gastaldi, Pierre-Olivier Buclez, Kamel Mamchaoui, Luis Garcia, Cyrille Vaillend, and Aurélie Goyenvalle
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exon skipping ,U7snRNA ,adeno-associated viral vector ,gene therapy ,Duchenne muscular dystrophy ,mouse model ,Genetics ,QH426-470 ,Cytology ,QH573-671 - Abstract
Gene therapy and antisense approaches hold promise for the treatment of Duchenne muscular dystrophy (DMD). The advantages of both therapeutic strategies can be combined by vectorizing antisense sequences into an adeno-associated virus (AAV) vector. We previously reported the efficacy of AAV-U7 small nuclear RNA (U7snRNA)-mediated exon skipping in the mdx mouse, the dys−/utr− mouse, and the golden retriever muscular dystrophy (GRMD) dog model. In this study, we examined the therapeutic potential of an AAV-U7snRNA targeting the human DMD exon 51, which could be applicable to 13% of DMD patients. A single injection of AAV9-U7 exon 51 (U7ex51) induces widespread and sustained levels of exon 51 skipping, leading to significant restoration of dystrophin and improvement of the dystrophic phenotype in the mdx52 mouse. However, levels of dystrophin re-expression are lower than the skipping levels, in contrast with previously reported results in the mdx mouse, suggesting that efficacy of exon skipping may vary depending on the targeted exon. Additionally, while low levels of exon skipping were measured in the brain, the dystrophin protein could not be detected, in line with a lack of improvement of their abnormal behavioral fear response. These results thus confirm the high therapeutic potential of the AAV-mediated exon-skipping approach, yet the apparent discrepancies between exon skipping and protein restoration levels suggest some limitations of this experimental model.
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- 2020
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5. Emotional behavior and brain anatomy of the mdx52 mouse model of Duchenne muscular dystrophy
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Amel Saoudi, Faouzi Zarrouki, Catherine Sebrié, Charlotte Izabelle, Aurélie Goyenvalle, and Cyrille Vaillend
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duchenne muscular dystrophy ,brain dystrophins ,dmd mouse model ,fear conditioning ,anxiety ,intellectual disability ,Medicine ,Pathology ,RB1-214 - Abstract
The exon-52-deleted mdx52 mouse is a critical model of Duchenne muscular dystrophy (DMD), as it features a deletion in a hotspot region of the DMD gene, frequently mutated in patients. Deletion of exon 52 impedes expression of several brain dystrophins (Dp427, Dp260 and Dp140), thus providing a key model for studying the cognitive impairment associated with DMD and testing rescuing strategies. Here, using in vivo magnetic resonance imaging and neurohistology, we found no gross brain abnormalities in mdx52 mice, suggesting that the neural dysfunctions in this model are likely at the level of brain cellular functionalities. Then, we investigated emotional behavior and fear learning performance of mdx52 mice compared to mdx mice that only lack Dp427 to focus on behavioral phenotypes that could be used in future comparative preclinical studies. mdx52 mice displayed enhanced anxiety and a severe impairment in learning an amygdala-dependent Pavlovian association. These replicable behavioral outcome measures are reminiscent of the internalizing problems reported in a quarter of DMD patients, and will be useful for preclinical estimation of the efficacy of treatments targeting brain dysfunctions in DMD.
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- 2021
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6. Efficacy and Safety Profile of Tricyclo-DNA Antisense Oligonucleotides in Duchenne Muscular Dystrophy Mouse Model
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Karima Relizani, Graziella Griffith, Lucía Echevarría, Faouzi Zarrouki, Patricia Facchinetti, Cyrille Vaillend, Christian Leumann, Luis Garcia, and Aurélie Goyenvalle
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Therapeutics. Pharmacology ,RM1-950 - Abstract
Antisense oligonucleotides (AONs) hold promise for therapeutic splice-switching correction in many genetic diseases. However, despite advances in AON chemistry and design, systemic use of AONs is limited due to poor tissue uptake and sufficient therapeutic efficacy is still difficult to achieve. A novel class of AONs made of tricyclo-DNA (tcDNA) is considered very promising for the treatment of Duchenne muscular dystrophy (DMD), a neuromuscular disease typically caused by frameshifting deletions or nonsense mutations in the gene-encoding dystrophin and characterized by progressive muscle weakness, cardiomyopathy, and respiratory failure in addition to cognitive impairment. Herein, we report the efficacy and toxicology profile of a 13-mer tcDNA in mdx mice. We show that systemic delivery of 13-mer tcDNA allows restoration of dystrophin in skeletal muscles and to a lower extent in the brain, leading to muscle function improvement and correction of behavioral features linked to the emotional/cognitive deficiency. More importantly, tcDNA treatment was generally limited to minimal glomerular changes and few cell necroses in proximal tubules, with only slight variation in serum and urinary kidney toxicity biomarker levels. These results demonstrate an encouraging safety profile for tcDNA, albeit typical of phosphorothiate AONs, and confirm its therapeutic potential for the systemic treatment of DMD patients. Keywords: antisense oligonucleotides, Duchenne muscular dystrophy, preclinical, splice switching, tcDNA-AONs
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- 2017
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7. Inhibitory SMAD6 interferes with BMP dependent generation of muscle progenitor cells and perturbs proximodistal pattern of murine limb muscles
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Hasan Asfour, Estelle Hirsinger, Raquel Rouco, Faouzi Zarrouki, Shinichiro Hayashi, Sandra Swist, Thomas Braun, Ketan Patel, Frédéric Relaix, Guillaume Andrey, Sigmar Stricker, Delphine Duprez, Amalia Stantzou, and Helge Amthor
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Molecular Biology ,Developmental Biology - Abstract
The mechanism of pattern formation during limb muscle development remains poorly understood. The canonical view holds that naïve limb muscle progenitor cells (MPCs) invade a pre-established pattern of muscle connective tissue, thereby forming individual muscles. Here we show that early murine embryonic limb MPCs highly accumulate pSMAD1/5/9, demonstrating active signaling of bone morphogenetic proteins (BMP) in these cells. Overexpression of inhibitory SMAD6 in limb MPCs abrogated BMP signaling, impaired their migration and proliferation, and accelerated myogenic lineage progression. Fewer primary myofibers developed, causing an aberrant proximodistal muscle pattern. Patterning was not disturbed when SMAD6 was overexpressed in differentiated muscle, implying that the proximodistal muscle pattern depends on BMP-mediated expansion of MPCs prior to their differentiation. We show that limb MPCs differentially express Hox genes, and Hox-expressing MPCs displayed active BMP signaling. SMAD6 overexpression caused loss of HOXA11 in early limb MPCs. In conclusion, our data show that BMP signaling controls expansion of embryonic limb MPC as a prerequisite for establishing the proximodistal muscle pattern, a process that involves expression of Hox genes.
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- 2023
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8. Abnormal Expression of Synaptic and Extrasynaptic GABA
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Faouzi, Zarrouki, Sébastien, Goutal, Ophélie, Vacca, Luis, Garcia, Nicolas, Tournier, Aurélie, Goyenvalle, and Cyrille, Vaillend
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Dystrophin ,Mice, Inbred C57BL ,Muscular Dystrophy, Duchenne ,Mice ,Benzodiazepines ,Mice, Inbred mdx ,Animals ,Receptors, GABA-A ,gamma-Aminobutyric Acid - Abstract
Duchenne muscular dystrophy (DMD) is a neurodevelopmental disorder primarily caused by the loss of the full-length Dp427 dystrophin in both muscle and brain. The basis of the central comorbidities in DMD is unclear. Brain dystrophin plays a role in the clustering of central gamma-aminobutyric acid A receptors (GABA
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- 2022
9. Partial Restoration of Brain Dystrophin and Behavioral Deficits by Exon Skipping in the Muscular Dystrophy X-Linked (mdx) Mouse
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Faouzi Zarrouki, Karima Relizani, Flavien Bizot, Thomas Tensorer, Luis Garcia, Cyrille Vaillend, Aurélie Goyenvalle, Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), SQY Therapeutics, Centre Scientifique de Monaco (CSM), and European Project: 847826,H2020,H2020-SC1-2019-Two-Stage-RTD,BIND(2020)
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[SDV.BIO]Life Sciences [q-bio]/Biotechnology ,[SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Oligonucleotides ,[SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences ,Brain ,Exons ,Oligonucleotides, Antisense ,Dystrophin ,Muscular Dystrophy, Duchenne ,Disease Models, Animal ,Mice ,[SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication ,Neurology ,Mice, Inbred mdx ,Animals ,Tissue Distribution ,Neurology (clinical) - Abstract
International audience; Objectives: Duchenne muscular dystrophy is associated with various degrees of cognitive impairment and behavioral disturbances. Emotional and memory deficits also constitute reliable outcome measures to assess efficacy of treatments in the mdx mouse lacking the muscle and neuronal full-length dystrophins. The present study aimed to evaluate whether these deficits could be alleviated by the restoration of brain dystrophin.Methods: We performed intracerebroventricular administration of a new potent tricyclo-DNA antisense oligonucleotide (tcDNA-ASO) containing a full phosphodiester backbone conjugated to a palmitic acid moiety (tcDNA-ASO), designed to skip the mutated exon 23 of mdx mice.Results: We first show that the tcDNA-ASO rescues expression of brain dystrophin to 10-30% of wild-type levels and significantly reduces the abnormal unconditioned fear responses in mdx mice in a dose-dependent manner, 5 weeks post-injection. Exon skipping efficiency, ASO biodistribution, protein restoration and effect on the fear response were optimal with a dose of 400 μg at 6-7 weeks post-injection, with synaptic-like expression in brain tissues such as the hippocampus and amygdala. Furthermore, this dose of tcDNA-ASO restored long-term memory retention of mdx mice in an object recognition task, but only had minor effects on fear conditioning.Interpretation: These results suggest for the first time that postnatal re-expression of brain dystrophin could reverse or at least alleviate some cognitive deficits associated with Duchenne muscular dystrophy. ANN NEUROL 2022;92:213-229.
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- 2022
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10. Emotional behavior and brain anatomy of the mdx52 mouse model of Duchenne muscular dystrophy
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Cyrille Vaillend, Amel Saoudi, Catherine Sebrié, Aurélie Goyenvalle, Faouzi Zarrouki, Charlotte Izabelle, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), LaBoratoire d'Imagerie biOmédicale MultimodAle Paris-Saclay (BIOMAPS), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité BioMaps (BIOMAPS), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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musculoskeletal diseases ,Duchenne muscular dystrophy ,Neuromuscular Disease Models ,congenital, hereditary, and neonatal diseases and abnormalities ,Neuroscience (miscellaneous) ,Intellectual disability ,Medicine (miscellaneous) ,Fear conditioning ,Anxiety ,General Biochemistry, Genetics and Molecular Biology ,Dystrophin ,Mice ,Exon ,Immunology and Microbiology (miscellaneous) ,In vivo ,Pathology ,medicine ,Animals ,Humans ,RB1-214 ,Brain dystrophins ,medicine.diagnostic_test ,business.industry ,Brain ,Magnetic resonance imaging ,Exons ,medicine.disease ,Muscular Dystrophy, Duchenne ,Disease Models, Animal ,Mice, Inbred mdx ,Medicine ,Emotional behavior ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,DMD mouse model ,medicine.symptom ,business ,Neuroscience ,Research Article - Abstract
The exon-52-deleted mdx52 mouse is a critical model of Duchenne muscular dystrophy (DMD), as it features a deletion in a hotspot region of the DMD gene, frequently mutated in patients. Deletion of exon 52 impedes expression of several brain dystrophins (Dp427, Dp260 and Dp140), thus providing a key model for studying the cognitive impairment associated with DMD and testing rescuing strategies. Here, using in vivo magnetic resonance imaging and neurohistology, we found no gross brain abnormalities in mdx52 mice, suggesting that the neural dysfunctions in this model are likely at the level of brain cellular functionalities. Then, we investigated emotional behavior and fear learning performance of mdx52 mice compared to mdx mice that only lack Dp427 to focus on behavioral phenotypes that could be used in future comparative preclinical studies. mdx52 mice displayed enhanced anxiety and a severe impairment in learning an amygdala-dependent Pavlovian association. These replicable behavioral outcome measures are reminiscent of the internalizing problems reported in a quarter of DMD patients, and will be useful for preclinical estimation of the efficacy of treatments targeting brain dysfunctions in DMD., Summary: The mdx52 mouse model of Duchenne muscular dystrophy lacks brain Dp427 and Dp140 dystrophins, and exhibits emotional, behavioral and learning phenotypes that are relevant for use in preclinical studies of the disorder.
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- 2021
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11. BMP Signaling Determines the Proximodistal Pattern of Limb Muscles by Spatiotemporal Control of Myogenic Progenitor Cells
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Hasan Asfour, Estelle Hirsinger, Raquel Rouco, Faouzi Zarrouki, Arunima Murgai, Shinichiro Hayashi, Sandra Swist, Thomas Braun, Ketan Patel, Fred Relaix, Guillaume Andrey, Delphine Duprez, Sigmar Stricker, Amalia Stantzou, and Helge Amthor
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History ,Polymers and Plastics ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2021
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12. Identifying and Avoiding tcDNA-ASO Sequence-Specific Toxicity for the Development of DMD Exon 51 Skipping Therapy
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Philippine, Aupy, Lucía, Echevarría, Karima, Relizani, Faouzi, Zarrouki, Adrian, Haeberli, Marek, Komisarski, Thomas, Tensorer, Grégory, Jouvion, Fedor, Svinartchouk, Luis, Garcia, Aurélie, Goyenvalle, Gestionnaire, Hal Sorbonne Université, Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, SYNTHENA AG, Institut Pasteur [Paris] (IP), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Centre Scientifique de Monaco (CSM), Institut Pasteur [Paris], Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Université de Paris (UP), and Maladies génétiques d'expression pédiatrique (U933)
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Duchenne muscular dystrophy ,splice switching ,sequence-specific toxicity ,[SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,preclinical ,tcDNA-ASOs ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,antisense oligonucleotides ,Article - Abstract
International audience; Tricyclo-DNA (tcDNA) antisense oligonucleotides (ASOs) hold promise for therapeutic splice-switching applications and the treatment of Duchenne muscular dystrophy (DMD) in particular. We have previously reported the therapeutic potential of tcDNA-ASO in mouse models of DMD, highlighting their unique pharmaceutical properties and unprecedented uptake in many tissues after systemic delivery, including the heart and central nervous system. Following these encouraging results, we developed phosphorothioate (PS)-modified tcDNA-ASOs targeting the human dystrophin exon 51 (H51). Preliminary evaluation of H51 PS-tcDNA in mice resulted in unexpected acute toxicity following intravenous administration of the selected candidate. In vivo and in vitro assays revealed complement activation, prolonged coagulation times, and platelet activation, correlating with the observed toxicity. In this study, we identify a novel PS-tcDNA sequence-specific toxicity induced by the formation of homodimer-like structures and investigate the therapeutic potential of a detoxified PS-tcDNA targeting exon 51. Modification of the H51-PS-tcDNA sequence, while maintaining target specificity through wobble pairing, abolished the observed toxicity by preventing homodimer formation. The resulting detoxified wobble-tcDNA candidate did not affect coagulation or complement pathways any longer nor activated platelets in vitro and was well tolerated in vivo in mice, confirming the possibility to detoxify specific tcDNA-ASO candidates successfully.
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- 2020
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13. Gene Therapy for Central Nervous System in Duchenne Muscular Dystrophy
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Faouzi Zarrouki, Cyrille Vaillend, Ophélie Vacca, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Dongsheng Duan, Jerry R. Mendell
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Duchenne muscular dystrophy ,Dp427 ,Genetic enhancement ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Central nervous system ,medicine.disease_cause ,Dystrophin ,03 medical and health sciences ,0302 clinical medicine ,Adeno-associated virus ,Intellectual disability ,DMD ,medicine ,Neural cell ,030304 developmental biology ,0303 health sciences ,biology ,[SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior ,business.industry ,[SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences ,AAV ,medicine.disease ,Phenotype ,3. Good health ,medicine.anatomical_structure ,biology.protein ,business ,Neuroscience ,Dp71 ,030217 neurology & neurosurgery - Abstract
International audience; The development of molecular therapies enabling compensation of brain alterations in Duchenne muscular dystrophy is a major objective given the high level of functional impairment associated with intellectual disability and neuropsychiatric disorders in this syndrome. Functional and preclinical studies in mice lacking distinct brain dystrophins identified an accurate set of phenotypes, from the molecular to neurophysiological and behavioral levels, which can be used as markers of efficacy for brain gene therapy. Pioneer studies in this past decade provided encouraging results, demonstrating that both dmd-gene splice-switching correction and replacement strategies hold realistic prospects to rescue expression and function of the brain full-length (Dp427) or short C-terminal (Dp71) dystrophins responsible for variable degrees of cognitive impairment in DMD. Strategies that could correct or alleviate both muscle and brain dysfunctions entail selection of molecular tools able to cross the blood-brain barrier following systemic delivery, to largely spread in neural tissues, and to selectively target the neural cell types (neurons, astrocytes) that require rescued expression of distinct brain dystrophins. Recent breakthroughs show that this can be achieved by engineering naked antisense oligonucleotides with specific chemistries and/or adeno-associated virus vectors with selective capsid properties, thus raising new hopes to bring gene therapy closer to whole-body delivery and full treatment of DMD symptoms.
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- 2019
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14. BMP signaling regulates satellite cell-dependent postnatal muscle growth
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Thomas Braun, Etienne Mouisel, Céline Colnot, Amalia Stantzou, Faouzi Zarrouki, Sandra Swist, Fabien Le Grand, Cyriaque Beley, Frédéric Relaix, Ioanna Polydorou, Helge Amthor, Luis Garcia, Sonia Alonso-Martin, Carmen Birchmeier, Markus Schuelke, Anaïs Julien, Elija Schirwis, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Thérapie des maladies du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Instituto de Ciências Mathemàticas e de Computação [São Carlos] (ICMC-USP), Universidade de São Paulo = University of São Paulo (USP), Max Delbrueck Center for Molecular Medicine, Helmholtz-Gemeinschaft = Helmholtz Association, Groupe Myologie, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-16-CE14-0002,BMP-MYOSTEM,Régulation des cellules souches du muscle squelettique adulte par la signalisation des ' Bone morphogenetic proteins '(2016), ANR-13-BSV1-0011,Bone-Muscle-Repair,Interactions os-muscle au cours de la régénération musculosquelettique(2013), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universidade de São Paulo (USP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), IMRB - Institut Mondor de Recherche Biomédicale, Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Inst Malad Metabol & Cardiovasc, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Satellite Cells, Skeletal Muscle ,[SDV]Life Sciences [q-bio] ,Blotting, Western ,Muscle Fibers, Skeletal ,Biology ,Bone morphogenetic protein ,Real-Time Polymerase Chain Reaction ,03 medical and health sciences ,Mice ,Internal medicine ,medicine ,Myocyte ,Animals ,Progenitor cell ,Muscle, Skeletal ,Molecular Biology ,Cells, Cultured ,ComputingMilieux_MISCELLANEOUS ,Cell Proliferation ,Cell growth ,Skeletal muscle ,Stem Cells and Regeneration ,Immunohistochemistry ,Mice, Mutant Strains ,BMPR2 ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Bone Morphogenetic Proteins ,Female ,Signal transduction ,Stem cell ,Developmental Biology ,Signal Transduction - Abstract
Postnatal growth of skeletal muscle largely depends on the expansion and differentiation of resident stem cells, the so-called satellite cells. Here, we demonstrate that postnatal satellite cells express components of the bone morphogenetic protein (BMP) signaling machinery. Overexpression of noggin in postnatal mice (to antagonize BMP ligands), satellite cell-specific knockout of Alk3 (the gene encoding the BMP transmembrane receptor) or overexpression of inhibitory SMAD6 decreased satellite cell proliferation and accretion during myofiber growth, and ultimately retarded muscle growth. Moreover, reduced BMP signaling diminished the adult satellite cell pool. Abrogation of BMP signaling in satellite cell-derived primary myoblasts strongly diminished cell proliferation and upregulated the expression of cell cycle inhibitors p21 and p57. In conclusion, these results show that BMP signaling defines postnatal muscle development by regulating satellite cell-dependent myofiber growth and the generation of the adult muscle stem cell pool.
- Published
- 2017
- Full Text
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15. Abnormal Expression of Synaptic and Extrasynaptic GABAA Receptor Subunits in the Dystrophin-Deficient mdx Mouse
- Author
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Faouzi Zarrouki, Sébastien Goutal, Ophélie Vacca, Luis Garcia, Nicolas Tournier, Aurélie Goyenvalle, Cyrille Vaillend, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), LaBoratoire d'Imagerie biOmédicale MultimodAle Paris-Saclay (BIOMAPS), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Duchenne muscular dystrophy ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Organic Chemistry ,GABAergic synapses ,General Medicine ,western blots ,GABA A-receptor clustering ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,outcome measures ,PET brain imaging ,immunofluorescence ,GABAA-receptor clustering ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy - Abstract
International audience; Duchenne muscular dystrophy (DMD) is a neurodevelopmental disorder primarily caused by the loss of the full-length Dp427 dystrophin in both muscle and brain. The basis of the central comorbidities in DMD is unclear. Brain dystrophin plays a role in the clustering of central gamma-aminobutyric acid A receptors (GABAARs), and its loss in the mdx mouse alters the clustering of some synaptic subunits in central inhibitory synapses. However, the diversity of GABAergic alterations in this model is still fragmentary. In this study, the analysis of in vivo PET imaging of a benzodiazepine-binding site radioligand revealed that the global density of central GABAARs is unaffected in mdx compared with WT mice. In contrast, semi-quantitative immunoblots and immunofluorescence confocal imaging in tissue sections revealed complex and differential patterns of alterations of the expression levels and/or clustered distribution of a variety of synaptic and extrasynaptic GABAAR subunits in the hippocampus, cerebellum, cortex, and spinal cord. Hence, dystrophin loss not only affects the stabilization of synaptic GABAARs but also influences the subunit composition of GABAARs subtypes at both synaptic and extrasynaptic sites. This study provides new molecular outcome measures and new routes to evaluate the impact of treatments aimed at compensating alterations of the nervous system in DMD.
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