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PABPN1 gene therapy for oculopharyngeal muscular dystrophy

Author

Listed:
  • A. Malerba

    (School of Biological Sciences, Royal Holloway, University of London, Egham Hill)

  • P. Klein

    (Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l’Hôpital)

  • H. Bachtarzi

    (School of Biological Sciences, Royal Holloway, University of London, Egham Hill
    Present address: ERA Consulting (UK) Ltd. (European Regulatory Affairs), Twelvetrees Crescent, London E3 3JG, UK)

  • S. A. Jarmin

    (School of Biological Sciences, Royal Holloway, University of London, Egham Hill)

  • G. Cordova

    (Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l’Hôpital)

  • A. Ferry

    (Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l’Hôpital
    Sorbonne Paris Cité, Université Paris Descartes)

  • V. Strings

    (Benitec Biopharma)

  • M. Polay Espinoza

    (Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l’Hôpital)

  • K. Mamchaoui

    (Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l’Hôpital)

  • S. C. Blumen

    (Hillel Yaffe Medical Center, Hadera and Rappaport Faculty of Medicine, The Technion)

  • J. Lacau St Guily

    (Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l’Hôpital
    Faculty of Medicine and University Pierre-et-Marie-Curie, Paris VI, Tenon Hospital, Assistance Publique des Hopitaux de Paris)

  • V. Mouly

    (Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l’Hôpital)

  • M. Graham

    (Benitec Biopharma)

  • G. Butler-Browne

    (Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l’Hôpital)

  • D. A. Suhy

    (Benitec Biopharma)

  • C. Trollet

    (Sorbonne Universités, UPMC Univ Paris 06, UM76, INSERM U974, Institut de Myologie, CNRS FRE3617, 47 bd de l’Hôpital)

  • G. Dickson

    (School of Biological Sciences, Royal Holloway, University of London, Egham Hill)

Abstract

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, late-onset muscle disorder characterized by ptosis, swallowing difficulties, proximal limb weakness and nuclear aggregates in skeletal muscles. OPMD is caused by a trinucleotide repeat expansion in the PABPN1 gene that results in an N-terminal expanded polyalanine tract in polyA-binding protein nuclear 1 (PABPN1). Here we show that the treatment of a mouse model of OPMD with an adeno-associated virus-based gene therapy combining complete knockdown of endogenous PABPN1 and its replacement by a wild-type PABPN1 substantially reduces the amount of insoluble aggregates, decreases muscle fibrosis, reverts muscle strength to the level of healthy muscles and normalizes the muscle transcriptome. The efficacy of the combined treatment is further confirmed in cells derived from OPMD patients. These results pave the way towards a gene replacement approach for OPMD treatment.

Suggested Citation

  • A. Malerba & P. Klein & H. Bachtarzi & S. A. Jarmin & G. Cordova & A. Ferry & V. Strings & M. Polay Espinoza & K. Mamchaoui & S. C. Blumen & J. Lacau St Guily & V. Mouly & M. Graham & G. Butler-Browne, 2017. "PABPN1 gene therapy for oculopharyngeal muscular dystrophy," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14848
    DOI: 10.1038/ncomms14848
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    Cited by:

    1. Chady H. Hakim & Sandeep R. P. Kumar & Dennis O. Pérez-López & Nalinda B. Wasala & Dong Zhang & Yongping Yue & James Teixeira & Xiufang Pan & Keqing Zhang & Emily D. Million & Christopher E. Nelson & , 2021. "Cas9-specific immune responses compromise local and systemic AAV CRISPR therapy in multiple dystrophic canine models," Nature Communications, Nature, vol. 12(1), pages 1-12, December.

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