title: Gene delivery to mitochondria by targeting modified adenoassociated virus suppresses Leber's hereditary optic neuropathy in a mouse model.
abstract: To introduce DNA into mitochondria efficiently, we fused adenoassociated virus capsid VP2 with a mitochondrial targeting sequence to carry the mitochondrial gene encoding the human NADH ubiquinone oxidoreductase subunit 4 (ND4). Expression of WT ND4 in cells with the G11778A mutation in ND4 led to restoration of defective ATP synthesis. Furthermore, with injection into the rodent eye, human ND4 DNA levels in mitochondria reached 80% of its mouse homolog. The construct expressed in most inner retinal neurons, and it also suppressed visual loss and optic atrophy induced by a mutant ND4 homolog. The adenoassociated virus cassette accommodates genes of up to ∼5 kb in length, thus providing a platform for introduction of almost any mitochondrial gene and perhaps even allowing insertion of DNA encompassing large deletions of mtDNA, some associated with aging, into the organelle of adults.
authors.affiliation: Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.forename: Rajeshwari D
authors.initials: RD
authors.lastname: Koilkonda
authors.forename: Tsung-Han
authors.initials: TH
authors.lastname: Chou
authors.forename: Vittorio
authors.initials: V
authors.lastname: Porciatti
authors.forename: Sacide S
authors.initials: SS
authors.lastname: Ozdemir
authors.forename: Vince
authors.initials: V
authors.lastname: Chiodo
authors.forename: Sanford L
authors.initials: SL
authors.lastname: Boye
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Boye
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.forename: Alfred S
authors.initials: AS
authors.lastname: Lewin
authors.forename: John
authors.initials: J
authors.lastname: Guy
mesh_terms: D000818:Animals; D036022:Capsid Proteins / Q000378:metabolism; D000229:Dependovirus / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000235:genetics*; D009841:Oligonucleotides / Q000235:genetics; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics / Q000628:therapy*; D010957:Plasmids / Q000235:genetics; D017354:Point Mutation / Q000235:genetics; D012160:Retina / Q000378:metabolism*; D014162:Transfection
chemical_list: D036022:Capsid Proteins; C098483:NADH dehydrogenase subunit 4; D009841:Oligonucleotides; D009245:NADH Dehydrogenase