Effective AAV-mediated gene therapy in a mouse model of ethylmalonic encephalopathy.
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.
Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology IRCCS, Milan, Italy.
Ivano
I
Di Meo
Alberto
A
Auricchio
Costanza
C
Lamperti
Alberto
A
Burlina
Carlo
C
Viscomi
Massimo
M
Zeviani
D000818:Animals; D020739:Brain Diseases, Metabolic, Inborn / Q000473:pathology / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics*; D049308:Dioxygenases / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics*; D011693:Purpura / Q000473:pathology / Q000628:therapy*; D013885:Thiosulfates / Q000097:blood; D016896:Treatment Outcome
D024101:Mitochondrial Proteins; D013885:Thiosulfates; D049308:Dioxygenases; C538757:ETHE1 protein, mouse; C477654:sulfur dioxygenase