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1. Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds

Author

Christophe Battail, Mark A. Tarnopolsky, Jean-François Deleuze, Magdalena Matloka, Arnaud Jollet, Arnaud F. Klein, Naira Naouar, Anne Boland, Frédérique Edom-Vovard, Micaela Polay Espinoza, Audrey Bazinet, Frédérique Rau, Jack Puymirat, Kamel Mamchaoui, Denis Furling, Ludovic Arandel, Vincent Mouly, Damily De Dea Diniz, Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Myologie, 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), McMaster University [Hamilton, Ontario], Centre hospitalier universitaire de Québec (CHUQ), Centre Hospitalier Universitaire de Québec, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de recherche en Myologie – U974 SU-INSERM, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Male, Muscle Fibers, Skeletal, Myotonic dystrophy, Drug Evaluation, Preclinical, Medicine (miscellaneous), lcsh:Medicine, medicine.disease_cause, Immunology and Microbiology (miscellaneous), Expanded repeats, Myocyte, Child, Cell Line, Transformed, Mutation, Nuclear aggregates, Middle Aged, 3. Good health, Cell biology, RNA splicing, Muscle cell line, Female, lcsh:RB1-214, Adult, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, Therapeutic compounds, Neuroscience (miscellaneous), Context (language use), [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, lcsh:Pathology, Humans, Resource Article, Muscle, Skeletal, MyoD Protein, Alternative splicing, lcsh:R, RNA, Fibroblasts, Oligonucleotides, Antisense, medicine.disease, Dd, Molecular biology, 030104 developmental biology, Cell culture, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the in vitro effects of compounds on RNA toxicity associated with myotonic dystrophy mutations., Summary: Myotonic dystrophy muscle cell models displaying characteristic disease-associated molecular features can be used to investigate molecular pathophysiological mechanisms and evaluate therapeutic approaches.

Published
2017

2. Dystrophin rescue by trans-splicing: a strategy for DMD genotypes not eligible for exon skipping approaches

Author

Graziella Griffith, Guillaume Precigout, Stéphanie Lorain, Luis Garcia, Thomas Voit, Maëva Le Hir, Susanne Philippi, Arnaud Jollet, Cécile Peccate, and Kamel Mamchaoui

Subjects
musculoskeletal diseases, mdx mouse, congenital, hereditary, and neonatal diseases and abnormalities, Genotype, Duchenne muscular dystrophy, Genetic Vectors, Muscle Fibers, Skeletal, Trans-Splicing, Dystrophin, Exon, Mice, Genetics, medicine, Animals, Humans, RNA, Messenger, biology, Muscles, MRNA stabilization, Exons, Dependovirus, medicine.disease, Exon skipping, Introns, Muscular Dystrophy, Duchenne, RNA splicing, Synthetic Biology and Chemistry, biology.protein, Mice, Inbred mdx, NIH 3T3 Cells, RNA Splice Sites, Minigene
Abstract

RNA-based therapeutic approaches using splice-switching oligonucleotides have been successfully applied to rescue dystrophin in Duchenne muscular dystrophy (DMD) preclinical models and are currently being evaluated in DMD patients. Although the modular structure of dystrophin protein tolerates internal deletions, many mutations that affect nondispensable domains of the protein require further strategies. Among these, trans-splicing technology is particularly attractive, as it allows the replacement of any mutated exon by its normal version as well as introducing missing exons or correcting duplication mutations. We have applied such a strategy in vitro by using cotransfection of pre-trans-splicing molecule (PTM) constructs along with a reporter minigene containing part of the dystrophin gene harboring the stop-codon mutation found in the mdx mouse model of DMD. Optimization of the different functional domains of the PTMs allowed achieving accurate and efficient trans-splicing of up to 30% of the transcript encoded by the cotransfected minigene. Optimized parameters included mRNA stabilization, choice of splice site sequence, inclusion of exon splice enhancers and artificial intronic sequence. Intramuscular delivery of adeno-associated virus vectors expressing PTMs allowed detectable levels of dystrophin in mdx and mdx4Cv, illustrating that a given PTM can be suitable for a variety of mutations.

Published
2013

3. Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy

Author

Didier Auboeuf, Masayuki Nakamori, Fernande Freyermuth, Chantal Sellier, Arnaud Jollet, Yosuke Kokunai, Muriel Philipps, Nicolas Charlet-Berguerand, Yoshihiro Kino, Amandine Campan-Fournier, Masanori P. Takahashi, John W. Day, Takashi Kimura, Denis Duboc, Kuang-Yung Lee, Shoichi Ishiura, Vincent Lacroix, Eric T. Wang, Harutoshi Fujimura, Shin Inada, Takashi Ashihara, Vincent Navratil, Bernard Jost, Thomas Zimmer, Hideki Mochizuki, Thomas Linke, Ludovic Arandel, Adolfo López de Munain, Maurice S. Swanson, Kazuo Nakazawa, Nobuyuki Nukina, Karim Wahbi, Emilie Chautard, Serge Vicaire, Hideki Itoh, Frédérique Rau, Denis Furling, Keiji Imoto, Christelle Thibault, François Deryckere, Tsuyoshi Matsumura, Bjarne Udd, Minoru Horie, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Myologie, 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), Osaka University [Osaka], Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany], Meiji Pharmaceutical University, University of Tampere [Finland], University of Helsinki, University of Vaasa, Stanford University, Service de Cardiologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Toneyama National Hospital, Intégrité du génome, Ecole Supérieure de Biotechnologie de Strasbourg (ESBS), Université de Strasbourg (UNISTRA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Hyogo Medical College, Doshisha University [Kyoto], The University of Tokyo (UTokyo), Baobab, Département PEGASE [LBBE] (PEGASE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Hospices Civils de Lyon (HCL), Pôle Rhône-Alpin de BioInformatique [Lyon] (PRABI), Université de Lyon-Université de Lyon, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Shiga University of Medical Science, National Institute for Physiological Science, Chang Gung Memorial Hospital [Taipei] (CGMH), University of Florida [Gainesville] (UF), Onekin [Donostia], University of the Basque Country [Bizkaia] (UPV/EHU), National cerebral and cardiovascular center research institute, 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), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), HAL UPMC, Gestionnaire, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), University Graduate School of Medicine [Osaka, Japan], Vaasa Central Hospital, Université Paris Descartes - Paris 5 (UPD5), Pôle Rhône Alpes de Bioinformatique, Université de Lyon, National Institute for Physiological Sciences, Donostia Hospital Universitario San Sebastian, Medicum, Department of Medical and Clinical Genetics, Université de Strasbourg - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC) - AFM - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Friedrich Schiller Universität [Jena, Germany], University of Helsinki [Helsinki], ARC Centre of Excellence for Coral Reef Studies (CoralCoE), James Cook University (JCU), Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Cochin [APHP], The University of Tokyo, Ecole Supérieure de Biotechnologie de Strasbourg - Centre National de la Recherche Scientifique (CNRS), Institut de Physique Théorique - UMR CNRS 3681 (IPHT), Commissariat à l'énergie atomique et aux énergies alternatives (CEA) - Université Paris-Saclay - Centre National de la Recherche Scientifique (CNRS), RIKEN, Doshisha University, University of Tokyo [Tokyo], Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria) - Institut National de Recherche en Informatique et en Automatique (Inria), CNRS UM5558, Laboratoire de Biométrie et Biologie Evolutive, Université Lyon 1, Hospices Civils de Lyon, Pôle Rhône-Alpes de Bio-Informatique (PRABI), Université Claude Bernard (Lyon 1) (UCBL1), Centre de Recherche en Cancérologie de Lyon (CRCL), Centre National de la Recherche Scientifique (CNRS) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Claude Bernard Lyon 1 (UCBL) - Centre Léon Bérard [Lyon], Kavli Institute for Astronomy and Astrophysics, Peking University [Beijing], Max Planck Institut für Gravitationsphysik, Albert Einstein Institut, University of Florida [Gainesville], Experimental Unit, Donostia Hospital, Kwansei Gakuin University, Kwansei gakuin University, Key Laboratory for Electromagnetic Processing of Materials, Northeastern University [Shenyang], Laboratoire de l'intégration, du matériau au système (IMS), Institut Polytechnique de Bordeaux - Université Sciences et Technologies - Bordeaux 1 - Centre National de la Recherche Scientifique (CNRS), AFM - Commissariat à l'énergie atomique et aux énergies alternatives (CEA) - Centre National de la Recherche Scientifique (CNRS) - Université Pierre et Marie Curie - Paris 6 (UPMC) - Assistance publique - Hôpitaux de Paris (AP-HP) - Institut National de la Santé et de la Recherche Médicale (INSERM), and Department of Materials Science, Graduate School of Engineering, Osaka Prefecture University, Sakai, Osaka

Subjects
0301 basic medicine, Male, Xenopus, [SDV]Life Sciences [q-bio], General Physics and Astronomy, RNA-binding protein, Sodium Channels, NAV1.5 Voltage-Gated Sodium Channel, Exon, chemistry.chemical_compound, MBNL1, Myotonic Dystrophy, Muscular dystrophy, ComputingMilieux_MISCELLANEOUS, Multidisciplinary, CHLORIDE CHANNEL, RNA-Binding Proteins, Exons, STRUCTURAL INSIGHTS, MOUSE MODEL, Middle Aged, Cell biology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV] Life Sciences [q-bio], RNA splicing, cardiovascular system, SKELETAL-MUSCLE, Female, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Science, Molecular Sequence Data, Biology, CTG REPEAT, Myotonic dystrophy, BRUGADA-SYNDROME, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Heart Conduction System, Internal medicine, Cardiac conduction, medicine, Animals, Humans, Computer Simulation, cardiovascular diseases, Nucleotide Motifs, TYPE-1, Aged, MUSCLEBLIND PROTEINS, Binding Sites, Base Sequence, PRE-MESSENGER-RNA, Alternative splicing, Arrhythmias, Cardiac, General Chemistry, medicine.disease, MUSCULAR-DYSTROPHY, Electrophysiological Phenomena, Alternative Splicing, 030104 developmental biology, Endocrinology, HEK293 Cells, chemistry, 3111 Biomedicine
Abstract

Myotonic dystrophy (DM) is caused by the expression of mutant RNAs containing expanded CUG repeats that sequester muscleblind-like (MBNL) proteins, leading to alternative splicing changes. Cardiac alterations, characterized by conduction delays and arrhythmia, are the second most common cause of death in DM. Using RNA sequencing, here we identify novel splicing alterations in DM heart samples, including a switch from adult exon 6B towards fetal exon 6A in the cardiac sodium channel, SCN5A. We find that MBNL1 regulates alternative splicing of SCN5A mRNA and that the splicing variant of SCN5A produced in DM presents a reduced excitability compared with the control adult isoform. Importantly, reproducing splicing alteration of Scn5a in mice is sufficient to promote heart arrhythmia and cardiac-conduction delay, two predominant features of myotonic dystrophy. In conclusion, misregulation of the alternative splicing of SCN5A may contribute to a subset of the cardiac dysfunctions observed in myotonic dystrophy., Patients with myotonic dystrophy (MD) suffer from severe cardiac issues of unknown aetiology. Freyermuth et al. show that fatal changes in cardiac electrophysiological properties in humans and mice with MD may arise from misregulation of the alternative splicing of the cardiac Na+ channel SCN5A transcript, resulting in expression of its fetal form.

Published
2016

4. Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy

Author

Olivier Delalande, Joelle Marie, Florent Dingli, Maurice S. Swanson, Denis Furling, Ludovic Arandel, George Dickson, Kuang-Yung Lee, Cécile Peccate, Arnaud Jollet, Laetitita Ramanoudjame, Stéphanie Lorain, Takis Athanasopoulos, Taeyoung Koo, Edor Kabashi, Elisabeth Le Rumeur, Arnaud Ferry, Damarys Loew, Jeanne Lainé, Frédérique Rau, Valérie Allamand, 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), département de physiologie, Université Pierre et Marie Curie - Paris 6 (UPMC), 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), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Spectrométrie de Masse des Protéines, Institut Curie [Paris], Department of Molecular Genetics and Microbiology and the Center for NeuroGenetics, University of Florida [Gainesville] (UF), Department of Neurology, Chang Gung Memorial Hospital [Taipei] (CGMH), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), School of Biological Sciences, Royal Holloway [University of London] (RHUL), This work was supported by the Association Française contre les Myopathies/AFM-Telethon (D.F.), UPMC Emergence (D.F.) and NIH AR046799 (M.S.S) grants., Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), 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)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
[SDV]Life Sciences [q-bio], Muscle Fibers, Skeletal, General Physics and Astronomy, Muscle Proteins, Dystrophin, chemistry.chemical_compound, Exon, Mice, 0302 clinical medicine, Tandem Mass Spectrometry, MBNL1, Homeostasis, Myotonic Dystrophy, Zebrafish, 0303 health sciences, Multidisciplinary, Gene Expression Regulation, Developmental, RNA-Binding Proteins, Exons, Immunohistochemistry, Cell biology, Sarcoplasmic Reticulum, Biological sciences, RNA splicing, RNA Splicing Factors, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, RNA Splicing, Biology, Real-Time Polymerase Chain Reaction, Myotonic dystrophy, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Medical research, medicine, Animals, Humans, Immunoprecipitation, 030304 developmental biology, Alternative splicing, Membrane Proteins, General Chemistry, Zebrafish Proteins, medicine.disease, biology.organism_classification, Molecular biology, Microscopy, Electron, chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, 030217 neurology & neurosurgery, Chromatography, Liquid
Abstract

Myotonic Dystrophy type 1 (DM1) is a dominant neuromuscular disease caused by nuclear-retained RNAs containing expanded CUG repeats. These toxic RNAs alter the activities of RNA splicing factors resulting in alternative splicing misregulation and muscular dysfunction. Here we show that the abnormal splicing of DMD exon 78 found in dystrophic muscles of DM1 patients is due to the functional loss of MBNL1 and leads to the re-expression of an embryonic dystrophin in place of the adult isoform. Forced expression of embryonic dystrophin in zebrafish using an exon-skipping approach severely impairs the mobility and muscle architecture. Moreover, reproducing Dmd exon 78 missplicing switch in mice induces muscle fibre remodelling and ultrastructural abnormalities including ringed fibres, sarcoplasmic masses or Z-band disorganization, which are characteristic features of dystrophic DM1 skeletal muscles. Thus, we propose that splicing misregulation of DMD exon 78 compromises muscle fibre maintenance and contributes to the progressive dystrophic process in DM1., The splicing of the penultimate exon of the dystrophin gene is developmentally regulated. Here the authors show that the dysregulation of this exon's splicing leads to the expression of an embryonic dystrophin form with a C-terminus distinct from the adult isoform, which leads to muscle wasting in zebrafish and mice.

Published
2015

5. Selective silencing of mutated mRNAs in DM1 by using modified hU7-snRNAs

Author

Luis Garcia, Virginie Francois, Arnaud Jollet, Denis Furling, Arnaud F. Klein, Camille Lemercier, Cyriaque Beley, Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Centre de recherche en Myologie – U974 SU-INSERM

Subjects
[SDV.BIO]Life Sciences [q-bio]/Biotechnology, [SDV]Life Sciences [q-bio], Mutant, Protein Serine-Threonine Kinases, Biology, Myotonic dystrophy, Myotonin-Protein Kinase, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Structural Biology, RNA, Small Nuclear, medicine, Humans, Myotonic Dystrophy, Gene silencing, Gene Silencing, RNA, Messenger, Allele, Molecular Biology, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetics, 0303 health sciences, DNA Repeat Expansion, RNA, medicine.disease, Alternative Splicing, RNA splicing, Genetic Engineering, 030217 neurology & neurosurgery, Function (biology)
Abstract

We describe a function for modified human U7 small nuclear RNAs (hU7-snRNAs) distinct from modification of pre-mRNA splicing events. Engineered hU7-snRNAs containing a poly-CAG antisense sequence targeting the expanded CUG repeats of mutant DMPK transcripts in myotonic dystrophy caused specific degradation of pathogenic DMPK mRNAs without affecting the products of wild-type DMPK alleles. Abolition of the RNA gain-of-function toxicity that is responsible for pathogenesis supports the use of hU7-snRNAs for gene silencing in RNA-dominant disorders in which expanded repeats are expressed.

Published
2010

6. New synthetic glycolipids for targeted gene transfer: synthesis, formulation in lipoplexes and specific interaction with lectin

Author

Daniel Scherman, Virginie Escriou, Claude Monneret, Michel Azoulay, Arnaud Jollet, and Marie Carrière

Subjects
Genetic enhancement, Chemistry, Pharmaceutical, Gene Transfer Techniques, Pharmaceutical Science, Lectin, General Medicine, Biology, Gene delivery, Ligand (biochemistry), carbohydrates (lipids), chemistry.chemical_compound, Glycolipid, chemistry, Biochemistry, In vivo, Cell Line, Tumor, Lectins, Gene Targeting, Liposomes, biology.protein, Humans, lipids (amino acids, peptides, and proteins), Surface charge, Glycolipids, DNA
Abstract

Nonviral gene delivery systems are a promising approach for gene therapy applications, despite their low in vivo gene transfer efficiency. One approach to enhance this efficiency is to incorporate targeting elements into cationic lipid/DNA complexes (lipoplexes). Ligand-containing lipoplexes have to retain their efficiency while exposing accessible ligand on their surface. Physicochemical properties (particle size, surface charge, and efficacy of DNA complexation) of the lipoplexes largely determine their gene transfer efficiency. We synthesized glycolipids with various galactosylated head ligand and incorporated them into lipoplexes. We showed that incorporation of up to 33% mol of glycolipid did not change the physicochemical properties of lipoplexes. Some of our glycolipids yielded lipoplexes whose galactosyl heads were well exposed on the surface as demonstrated by a strong interaction with Ricinus communis agglutinin. Glycolipid-containing lipoplexes gave an efficient gene transfer on hepatocytes, although no ligand-targeted transfection could be observed.

Published
2005

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