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

EMBO Molecular Medicine

Ivano Di Meo¹  Alberto Auricchio⁴  Costanza Lamperti¹  Alberto Burlina²  Carlo Viscomi³ 

[1] Unit of Molecular Neurogenetics, The Foundation “Carlo Besta” Institute of Neurology IRCCS, Milan, Italy;Division of Inherited Metabolic Diseases, Department of Pediatrics, University of Padua School of Medicine, Padua, Italy;E-mail address: 关键词: adeno‐associated virus;    ethylmalonic encephalopathy;    gene therapy;    hydrogen sulfide;    mitochondrial disease;   

DOI  :  10.1002/emmm.201201433

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
Copyright © 2012 EMBO Molecular Medicine

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.