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  • A single epidermal stem cell strategy for safe ex vivo gene therapy
    1. Stéphanie Droz‐Georget Lathion1,2,
    2. Ariane Rochat1,2,
    3. Graham Knott3,
    4. Alessandra Recchia4,
    5. Danielle Martinet5,
    6. Sara Benmohammed6,
    7. Nicolas Grasset1,2,
    8. Andrea Zaffalon1,2,
    9. Nathalie Besuchet Schmutz5,
    10. Emmanuelle Savioz‐Dayer1,2,
    11. Jacques Samuel Beckmann5,6,
    12. Jacques Rougemont7,
    13. Fulvio Mavilio4,8 and
    14. Yann Barrandon*,1,2
    1. 1Department of Experimental Surgery, Lausanne University Hospital (CHUV), Lausanne, Switzerland
    2. 2Laboratory of Stem Cell Dynamics, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
    3. 3Interdisciplinary Center for Electron Microscopy, Faculty of Life Sciences EPFL, Lausanne, Switzerland
    4. 4Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
    5. 5Service de Génétique Médicale, Lausanne University Hospital (CHUV), Lausanne, Switzerland
    6. 6Bioinformatics and Biostatistics Core Facility, Faculty of Life Sciences EPFL, Lausanne, Switzerland
    7. 7Department of Medical Genetics, Université de Lausanne, Lausanne, Switzerland
    8. 8Genethon, Evry, France
    1. *Corresponding author. Tel: +41 21 314 24 61; Fax: +41 21 314 24 68; E‐mail: yann.barrandon{at}epfl.ch

    First time demonstration of a safe clonal strategy for ex vivo gene therapy before autologous transduced cells are transplanted into patients. Using recessive dystrophic epidermolysis bullosa (RDEB) COL7A1 corrected epidermal cloned stem cells as proof of principle, this strategy proves promising for clinical applications.

    Synopsis

    First time demonstration of a safe clonal strategy for ex vivo gene therapy before autologous transduced cells are transplanted into patients. Using recessive dystrophic epidermolysis bullosa (RDEB) COL7A1 corrected epidermal cloned stem cells as proof of principle, this strategy proves promising for clinical applications.

    • Assessment of safety and efficacy of an ex vivo gene therapy product derived from a single epidermal stem cell transduced with a gene of interest.

    • A clonal strategy was the best method to fulfil stringent safety regulatory requirements for ex vivo gene therapy.

    • Long‐term regeneration of anchoring fibrils from the progeny of a single genetically corrected epidermal stem cell from a patient with RDEB (type VII collagen deficiency) transplanted onto immunodeficient mice.

    • cell therapy
    • regulatory affairs
    • stem cells
    • wound healing
    • Received June 18, 2014.
    • Revision received January 8, 2015.
    • Accepted January 21, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Stéphanie Droz‐Georget Lathion, Ariane Rochat, Graham Knott, Alessandra Recchia, Danielle Martinet, Sara Benmohammed, Nicolas Grasset, Andrea Zaffalon, Nathalie Besuchet Schmutz, Emmanuelle Savioz‐Dayer, Jacques Samuel Beckmann, Jacques Rougemont, Fulvio Mavilio, Yann Barrandon
  • Single stem cell gene therapy for genetic skin disease
    1. Jean‐Christophe Larsimont1 and
    2. Cédric Blanpain (cedric.Blanpain{at}ulb.ac.be) 1,2
    1. 1Université Libre de Bruxelles IRIBHM, Brussels, Belgium
    2. 2WELBIO Université Libre de Bruxelles, Brussels, Belgium

    Stem cell gene therapy followed by transplantation into damaged regions of the skin has been successfully used to treat genetic skin blistering disorder. Usually, many stem cells are virally transduced to obtain a sufficient number of genetically corrected cells required for successful transplantation, as genetic insertion in every stem cell cannot be precisely defined. In this issue of EMBO Molecular Medicine, Droz‐Georget Lathion et al developed a new strategy for ex vivo single cell gene therapy that allows extensive genomic and functional characterization of the genetically repaired individual cells before they can be used in clinical settings.

    See also: S Droz-Georget Lathion et al

    In this issue of EMBO Molecular Medicine, Droz‐Georget Lathion et al developed a new strategy for ex vivo single‐cell gene therapy that allows extensive genomic and functional characterization of the genetically repaired cells before they can be used in clinical settings.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Jean‐Christophe Larsimont, Cédric Blanpain
  • In vivo generation of a mature and functional artificial skeletal muscle
    1. Claudia Fuoco1,
    2. Roberto Rizzi2,3,
    3. Antonella Biondo1,
    4. Emanuela Longa4,
    5. Anna Mascaro4,
    6. Keren Shapira‐Schweitzer6,
    7. Olga Kossovar6,
    8. Sara Benedetti4,
    9. Maria L Salvatori1,
    10. Sabrina Santoleri19,
    11. Stefano Testa1,
    12. Sergio Bernardini1,
    13. Roberto Bottinelli4,7,
    14. Claudia Bearzi2,3,
    15. Stefano M Cannata*,1,
    16. Dror Seliktar6,
    17. Giulio Cossu*,5,8 and
    18. Cesare Gargioli*,1,2
    1. 1Department of Biology, Tor Vergata Rome University, Rome, Italy
    2. 2IRCCS MultiMedica, Milan, Italy
    3. 3Cell Biology and Neurobiology Institute, National Research Council of Italy, Rome, Italy
    4. 4Department of Molecular Medicine and Interdepartmental Centre for Research in Sport Biology and Medicine, University of Pavia, Pavia, Italy
    5. 5Department of Cell and Developmental Biology, University College London, London, UK
    6. 6Faculty of Biomedical Engineering, Technion—Israel Institute of Technology, Haifa, Israel
    7. 7Fondazione Salvatore Maugeri (IRCCS), Scientific Institute of Pavia, Pavia, Italy
    8. 8Institute of Inflammation and Repair, University of Manchester, Manchester, UK
    9. 9Biocenter Oulu, Institute of Biomedicine, University of Oulu Finland
    1. * Corresponding author. Tel: +39 6 72594815; E‐mail: cesare.gargioli{at}uniroma2.it

      Corresponding author. Tel: +44 161 3062526; E‐mail: giulio.cossu{at}manchester.ac.uk

      Corresponding author. Tel: +39 6 72594815; E‐mail: cannata{at}uniroma2.it

    This study proposes a novel and efficient strategy for skeletal muscle tissue engineering based on in vitro mixing of mouse or human mesoangioblasts with a PEG‐fibrinogen, which promotes their survival and differentiation into muscle.

    Synopsis

    This study proposes a novel and efficient strategy for skeletal muscle tissue engineering based on in vitro mixing of mouse or human mesoangioblasts with a PEG‐fibrinogen, which promotes their survival and differentiation into muscle.

    • Upon graft implantation between the skin and the outer surface of the tibialis anterior, mature and aligned myofibres formed within a few weeks as a complete and functional extra muscle.

    • Upon graft replacement of an almost completely ablated tibialis anterior, a new skeletal muscle very similar to the ablated one formed within a few weeks.

    • Placental‐derived growth factor‐lentivirus transduction of muscle cells prior to transplant stimulates blood vessel growth and contributes to in vivo cells survival and maturation.

    • This novel strategy opens up the possibility for patient‐specific muscle engineering in a large number of pathological conditions involving muscle tissue wasting.

    • artificial skeletal muscle
    • mesoangioblasts
    • PEG‐fibrinogen
    • Received March 13, 2014.
    • Revision received January 16, 2015.
    • Accepted January 22, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Claudia Fuoco, Roberto Rizzi, Antonella Biondo, Emanuela Longa, Anna Mascaro, Keren Shapira‐Schweitzer, Olga Kossovar, Sara Benedetti, Maria L Salvatori, Sabrina Santoleri, Stefano Testa, Sergio Bernardini, Roberto Bottinelli, Claudia Bearzi, Stefano M Cannata, Dror Seliktar, Giulio Cossu, Cesare Gargioli
  • A high‐resolution genomic analysis of multidrug‐resistant hospital outbreaks of Klebsiella pneumoniae
    1. Hao Chung The1,,
    2. Abhilasha Karkey2,,
    3. Duy Pham Thanh1,
    4. Christine J Boinett3,
    5. Amy K Cain3,
    6. Matthew Ellington3,4,
    7. Kate S Baker3,
    8. Sabina Dongol2,
    9. Corinne Thompson1,5,
    10. Simon R Harris3,
    11. Thibaut Jombart6,
    12. Tu Le Thi Phuong1,
    13. Nhu Tran Do Hoang1,
    14. Tuyen Ha Thanh1,
    15. Shrijana Shretha2,
    16. Suchita Joshi2,
    17. Buddha Basnyat2,
    18. Guy Thwaites1,5,
    19. Nicholas R Thomson3,7,,
    20. Maia A Rabaa1,8, and
    21. Stephen Baker*,1,5,7,
    1. 1The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam
    2. 2Patan Academy of Health Sciences, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Kathmandu, Nepal
    3. 3The Wellcome Trust Sanger Institute, Hinxton Cambridge, UK
    4. 4Addenbrooke's Hospital, Cambridge, UK
    5. 5Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK
    6. 6MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College, London, UK
    7. 7The London School of Hygiene and Tropical Medicine, London, UK
    8. 8Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, UK
    1. *Corresponding author. Tel: +84 8 39239210; E‐mail: sbaker{at}oucru.org
    1. These authors contributed equally to this work

    2. Joint senior authors

    Whole‐genome sequencing and further data analysis allowed for a comprehensive understanding of the emergence and spread of two highly virulent clones of drug‐resistant Klebsiella pneumonia bloodstream infections from one hospital in Kathmandu, Nepal.

    Synopsis

    Whole‐genome sequencing and further data analysis allowed for a comprehensive understanding of the emergence and spread of two highly virulent clones of drug‐resistant Klebsiella pneumonia bloodstream infections from one hospital in Kathmandu, Nepal.

    • MDR Klebsiella pneumoniae (Kp) can cause serious hospital outbreaks and can be associated with high mortality in hospitals in developing countries.

    • Whole‐genome sequencing (WGS) of Kp bloodstream infections was used to study localized transmission and genetic adaptation during a hospital outbreak in Nepal.

    • Genetic material specific to outbreak lineages permitted a retrospective temporal reconstruction of two Kp outbreak lineages across the hospital.

    • The added benefit of Kp WGS in this study was to dissect these outbreaks with extremely fine detail.

    • Genetic characterization of Kp causing bloodstream infections in hospitals in developing countries should be performed routinely to identify and isolate outbreaks early.

    • antimicrobial resistance
    • bloodstream infections
    • carbapenemases
    • Klebsiella pneumoniae
    • nosocomial infections
    • Received October 21, 2014.
    • Revision received January 19, 2015.
    • Accepted January 20, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Hao Chung The, Abhilasha Karkey, Duy Pham Thanh, Christine J Boinett, Amy K Cain, Matthew Ellington, Kate S Baker, Sabina Dongol, Corinne Thompson, Simon R Harris, Thibaut Jombart, Tu Le Thi Phuong, Nhu Tran Do Hoang, Tuyen Ha Thanh, Shrijana Shretha, Suchita Joshi, Buddha Basnyat, Guy Thwaites, Nicholas R Thomson, Maia A Rabaa, Stephen Baker
  • Metabolic and hypoxic adaptation to anti‐angiogenic therapy: a target for induced essentiality
    1. Alan McIntyre1 and
    2. Adrian L Harris*,1
    1. 1Hypoxia and angiogenesis Group, Department of Oncology Weatherall Institute of Molecular Medicine University of Oxford, Oxford, UK
    1. *Corresponding author. Tel: +44 1865 222457; Fax: +44 1865 222 431; E‐mail: aharris.lab{at}imm.ox.ac.uk

    Improving progression‐free survival in cancer: the importance of combining anti‐angiogenic therapy with inhibitors of hypoxic and metabolic adaptation to target induced essentiality and overcome tumour adaption.

    • angiogenesis
    • anti‐VEGF therapy
    • combination therapy
    • hypoxia
    • metabolism
    • Received November 15, 2014.
    • Revision received January 12, 2015.
    • Accepted January 27, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Alan McIntyre, Adrian L Harris
  • Atrial‐like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial‐selective pharmacology
    1. Harsha D Devalla*,1,
    2. Verena Schwach1,
    3. John W Ford2,
    4. James T Milnes2,
    5. Said El‐Haou2,
    6. Claire Jackson2,
    7. Konstantinos Gkatzis1,
    8. David A Elliott3,
    9. Susana M Chuva de Sousa Lopes1,4,
    10. Christine L Mummery1,
    11. Arie O Verkerk5 and
    12. Robert Passier*,1
    1. 1Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands
    2. 2Xention Ltd, Cambridge, UK
    3. 3Murdoch Childrens Research Institute Royal Children's Hospital, Melbourne, Vic., Australia
    4. 4Department for Reproductive Medicine, Ghent University Hospital, Ghent, Belgium
    5. 5Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
    1. * Corresponding author. Tel: +31 71 5269528; Fax: +31 71 5268289; E‐mail: h.d.devalla{at}lumc.nl

      Corresponding author. Tel: +31 71 5269359; Fax: +31 71 5268289; E‐mail: r.passier{at}lumc.nl

    Newly generated human embryonic stem cell‐derived atrial‐like cardiomyocytes resemble human atrial cardiomyocytes and prove to be a valuable model for pre‐clinical drug screenings to identify effective atrial‐selective compounds against atrial fibrillation.

    Synopsis

    Newly generated human embryonic stem cell‐derived atrial‐like cardiomyocytes resemble human atrial cardiomyocytes and prove to be a valuable model for pre‐clinical drug screenings to identify effective atrial‐selective compounds against atrial fibrillation.

    • Exogenous addition of retinoic acid drives differentiating human embryonic stem cells towards atrial‐like cardiomyocytes.

    • COUP‐TFI and COUP‐TFII are induced during atrial differentiation.

    • COUP‐TF transcription factors regulate atrial‐specific ion channel genes.

    • hESC‐atrial CMs respond to drugs targeting atrial‐selective ion channels.

    • arrhythmias
    • atrial cardiomyocytes
    • atrial fibrillation
    • COUP‐TF
    • ion channels
    • Received October 17, 2014.
    • Revision received January 18, 2015.
    • Accepted January 23, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Harsha D Devalla, Verena Schwach, John W Ford, James T Milnes, Said El‐Haou, Claire Jackson, Konstantinos Gkatzis, David A Elliott, Susana M Chuva de Sousa Lopes, Christine L Mummery, Arie O Verkerk, Robert Passier
  • A novel fragile X syndrome mutation reveals a conserved role for the carboxy‐terminus in FMRP localization and function
    1. Zeynep Okray1,2,3,
    2. Celine EF de Esch4,
    3. Hilde Van Esch2,
    4. Koen Devriendt2,
    5. Annelies Claeys1,2,
    6. Jiekun Yan1,2,
    7. Jelle Verbeeck1,2,
    8. Guy Froyen1,2,
    9. Rob Willemsen4,
    10. Femke MS de Vrij5 and
    11. Bassem A Hassan*,1,2,3
    1. 1VIB Center for the Biology of Disease, VIB, Leuven, Belgium
    2. 2Center for Human Genetics, University of Leuven School of Medicine and University Hospitals Leuven, Leuven, Belgium
    3. 3Program in Molecular and Developmental Genetics, Doctoral School of Biomedical Sciences, University of Leuven, Leuven, Belgium
    4. 4Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
    5. 5Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands
    1. *Corresponding author. Tel: +32 16 330752; E‐mail: bh{at}kuleuven.be

    A novel point mutation in the FMR1 gene was identified in a typical fragile X syndrome patient, suggesting that undiagnosed FXS patients with single point mutations may exist. Functional analysis shows an unexpected nuclear export role for the prematurely truncated protein.

    Synopsis

    A novel point mutation in the FMR1 gene was identified in a typical fragile X syndrome patient, suggesting that undiagnosed FXS patients with single point mutations may exist. Functional analysis shows an unexpected nuclear export role for the prematurely truncated protein.

    • Sequencing of a patient with typical FXS features reveals a point mutation in the FMR1 gene.

    • The resulting FMRP protein encodes a frameshifted sequence resulting in a nuclear/nucleolar localization signal and truncation of the C‐terminal region of FMRP.

    • Mutating the ectopic nucleolar localization signal or restoring the C‐terminus of the human protein results in normal FMRP sub‐cellular localization.

    • Overexpression of a patient‐mimicking protein in Drosophila neurons in vivo causes nuclear localization and novel axonal growth and guidance phenotypes.

    • Restoration of the C‐terminus rescues the localization and the normal activity of Drosophila FMRP.

    • axon guidance
    • Drosophila
    • fragile X syndrome
    • nuclear export
    • nucleolus
    • Received August 26, 2014.
    • Revision received December 19, 2014.
    • Accepted January 9, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Zeynep Okray, Celine EF de Esch, Hilde Van Esch, Koen Devriendt, Annelies Claeys, Jiekun Yan, Jelle Verbeeck, Guy Froyen, Rob Willemsen, Femke MS de Vrij, Bassem A Hassan