Effective AAV-mediated gene therapy in a mouse model of ethylmalonic encephalopathy

Authors

  • Ivano Di Meo,

    1. Unit of Molecular Neurogenetics, The Foundation “Carlo Besta” Institute of Neurology IRCCS, Milan, Italy
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  • Alberto Auricchio,

    1. Telethon Institute of Genetics and Medicine (TIGEM) and Division of Medical Genetics, Department of Pediatrics, “Federico II” University, Naples, Italy
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  • Costanza Lamperti,

    1. Unit of Molecular Neurogenetics, The Foundation “Carlo Besta” Institute of Neurology IRCCS, Milan, Italy
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  • Alberto Burlina,

    1. Division of Inherited Metabolic Diseases, Department of Pediatrics, University of Padua School of Medicine, Padua, Italy
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  • Carlo Viscomi,

    Corresponding author
    1. Unit of Molecular Neurogenetics, The Foundation “Carlo Besta” Institute of Neurology IRCCS, Milan, Italy
    • Carlo Viscomi, Tel: +39 02 23942611; Fax: +39 02 23942619

      Massimo Zeviani, Tel: +39 02 2394 2630; Fax: +39 02 23942619

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  • Massimo Zeviani

    Corresponding author
    1. Unit of Molecular Neurogenetics, The Foundation “Carlo Besta” Institute of Neurology IRCCS, Milan, Italy
    • Carlo Viscomi, Tel: +39 02 23942611; Fax: +39 02 23942619

      Massimo Zeviani, Tel: +39 02 2394 2630; Fax: +39 02 23942619

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Abstract

Ethylmalonic encephalopathy (EE) is an invariably fatal disease, characterized by the accumulation of hydrogen sulfide (H2S), a highly toxic compound. ETHE1, encoding sulfur dioxygenase (SDO), which takes part in the mitochondrial pathway that converts sulfide into harmless sulfate, is mutated in EE. The main source of H2S is the anaerobic bacterial flora of the colon, although in trace amount it is also produced by tissues, where it acts as a ‘gasotransmitter’. Here, we show that AAV2/8-mediated, ETHE1-gene transfer to the liver of a genetically, metabolically and clinically faithful EE mouse model resulted in full restoration of SDO activity, correction of plasma thiosulfate, a biomarker reflecting the accumulation of H2S, and spectacular clinical improvement. Most of treated animals were alive and well >6–8 months after birth, whereas untreated individuals live 26 ± 7 days. Our results provide proof of concept on the efficacy and safety of AAV2/8-mediated livergene therapy for EE, and alike conditions caused by the accumulation of harmful compounds in body fluids and tissues, which can directly be transferred to the clinic.

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