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.
| Original language | English |
|---|---|
| Pages (from-to) | 1008-1014 |
| Number of pages | 7 |
| Journal | EMBO Molecular Medicine |
| Volume | 4 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - Sep 2012 |
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Keywords
- Adeno-associated virus
- Ethylmalonic encephalopathy
- Gene therapy
- Hydrogen sulfide
- Mitochondrial disease
ASJC Scopus subject areas
- Molecular Medicine
Cite this
Effective AAV-mediated gene therapy in a mouse model of ethylmalonic encephalopathy. / Di Meo, Ivano; Auricchio, Alberto; Lamperti, Costanza; Burlina, Alberto; Viscomi, Carlo; Zeviani, Massimo.
In: EMBO Molecular Medicine, Vol. 4, No. 9, 09.2012, p. 1008-1014.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Effective AAV-mediated gene therapy in a mouse model of ethylmalonic encephalopathy
AU - Di Meo, Ivano
AU - Auricchio, Alberto
AU - Lamperti, Costanza
AU - Burlina, Alberto
AU - Viscomi, Carlo
AU - Zeviani, Massimo
PY - 2012/9
Y1 - 2012/9
N2 - 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.
AB - 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.
KW - Adeno-associated virus
KW - Ethylmalonic encephalopathy
KW - Gene therapy
KW - Hydrogen sulfide
KW - Mitochondrial disease
UR - http://www.scopus.com/inward/record.url?scp=84865725896&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84865725896&partnerID=8YFLogxK
U2 - 10.1002/emmm.201201433
DO - 10.1002/emmm.201201433
M3 - Article
C2 - 22903887
AN - SCOPUS:84865725896
VL - 4
SP - 1008
EP - 1014
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 9
ER -