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Neonatal gene therapy achieves sustained disease rescue of maple syrup urine disease in mice

Author

Listed:
  • Clément Pontoizeau

    (Paris Cité University
    Paris Cité University
    Inserm UMR_S1163, Institut Imagine)

  • Marcelo Simon-Sola

    (Inserm UMR_S1163, Institut Imagine)

  • Clovis Gaborit

    (Inserm UMR_S1163, Institut Imagine)

  • Vincent Nguyen

    (Inserm UMR_S1163, Institut Imagine)

  • Irina Rotaru

    (Inserm UMR_S1163, Institut Imagine)

  • Nolan Tual

    (Inserm UMR_S1163, Institut Imagine)

  • Pasqualina Colella

    (Généthon INTEGRARE UMR-S951, University of Evry)

  • Muriel Girard

    (Paris Cité University
    Inserm U1151, Institut Necker Enfants Malades)

  • Maria-Grazia Biferi

    (Sorbonne University, Inserm, Institute of Myology, Centre of Research in Myology)

  • Jean-Baptiste Arnoux

    (Paris Cité University)

  • Agnès Rötig

    (Inserm UMR_S1163, Institut Imagine)

  • Chris Ottolenghi

    (Paris Cité University
    Paris Cité University
    Inserm UMR_S1163, Institut Imagine)

  • Pascale Lonlay

    (Paris Cité University
    Inserm U1151, Institut Necker Enfants Malades)

  • Federico Mingozzi

    (Généthon INTEGRARE UMR-S951, University of Evry)

  • Marina Cavazzana

    (Inserm UMR_S1163, Institut Imagine
    Paris Cité University)

  • Manuel Schiff

    (Paris Cité University
    Inserm UMR_S1163, Institut Imagine)

Abstract

Maple syrup urine disease (MSUD) is a rare recessively inherited metabolic disorder causing accumulation of branched chain amino acids leading to neonatal death, if untreated. Treatment for MSUD represents an unmet need because the current treatment with life-long low-protein diet is challenging to maintain, and despite treatment the risk of acute decompensations and neuropsychiatric symptoms remains. Here, based on significant liver contribution to the catabolism of the branched chain amino acid leucine, we develop a liver-directed adeno-associated virus (AAV8) gene therapy for MSUD. We establish and characterize the Bckdha (branched chain keto acid dehydrogenase a)−/− mouse that exhibits a lethal neonatal phenotype mimicking human MSUD. Animals were treated at P0 with intravenous human BCKDHA AAV8 vectors under the control of either a ubiquitous or a liver-specific promoter. BCKDHA gene transfer rescued the lethal phenotype. While the use of a ubiquitous promoter fully and sustainably rescued the disease (long-term survival, normal phenotype and correction of biochemical abnormalities), liver-specific expression of BCKDHA led to partial, though sustained rescue. Here we show efficacy of gene therapy for MSUD demonstrating its potential for clinical translation.

Suggested Citation

  • Clément Pontoizeau & Marcelo Simon-Sola & Clovis Gaborit & Vincent Nguyen & Irina Rotaru & Nolan Tual & Pasqualina Colella & Muriel Girard & Maria-Grazia Biferi & Jean-Baptiste Arnoux & Agnès Rötig & , 2022. "Neonatal gene therapy achieves sustained disease rescue of maple syrup urine disease in mice," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30880-w
    DOI: 10.1038/s41467-022-30880-w
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