Gene Delivery to Mitochondria by Targeting Modified Adenoassociated Virus Suppresses Leber's Hereditary Optic Neuropathy in a Mouse Model

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2012 Apr 24

PMID 22523243

Citations 86

Authors

Hong Yu

Rajeshwari D Koilkonda

Tsung-Han Chou

Vittorio Porciatti

Sacide S Ozdemir

Vince Chiodo

Sanford L Boye

Shannon E Boye

William W Hauswirth

Alfred S Lewin

John Guy

Affiliations

Soon will be listed here.

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.

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