Open AccessEffective AAV‐mediated gene therapy in a mouse model of ethylmalonic encephalopathy
Author(s) -
Di Meo Ivano,
Auricchio Alberto,
Lamperti Costanza,
Burlina Alberto,
Viscomi Carlo,
Zeviani Massimo
Publication year - 2012
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201201433
Subject(s) - hydrogen sulfide , thiosulfate , biomarker , encephalopathy , gene , genetic enhancement , chemistry , sulfur , biology , medicine , cancer research , biochemistry , organic chemistry
Ethylmalonic encephalopathy (EE) is an invariably fatal disease, characterized by the accumulation of hydrogen sulfide (H 2 S), 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 H 2 S 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 H 2 S, 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.