title: Nuclear expression of mitochondrial ND4 leads to the protein assembling in complex I and prevents optic atrophy and visual loss.
abstract: Leber hereditary optic neuropathy is due to mitochondrial DNA mutations; in ~70% of all cases, a point mutation in the mitochondrial NADH dehydrogenase subunit 4, ND4, gene leads to central vision loss. We optimized allotopic expression (nuclear transcription of a gene that is normally transcribed inside the mitochondria) aimed at designing a gene therapy for ND4; its coding sequence was associated with the cis-acting elements of the human COX10 mRNA to allow the efficient mitochondrial delivery of the protein. After ocular administration to adult rats of a recombinant adeno-associated viral vector containing the human ND4 gene, we demonstrated that: (i) the sustained expression of human ND4 did not lead to harmful effects, instead the human protein is efficiently imported inside the mitochondria and assembled in respiratory chain complex I; (ii) the presence of the human protein in the experimental model of Leber hereditary optic neuropathy significantly prevents retinal ganglion cell degeneration and preserves both complex I function in optic nerves and visual function. Hence, the use of optimized allotopic expression is relevant for treating mitochondrial disorders due to mutations in the organelle genome.
authors.affiliation: INSERM, U968 , Paris, France ; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la, Vision , Paris, France ; CNRS, UMR_7210 , Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Cwerman-Thibault
authors.affiliation: INSERM, U968 , Paris, France ; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la, Vision , Paris, France ; CNRS, UMR_7210 , Paris, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Augustin
authors.affiliation: INSERM, U968 , Paris, France ; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la, Vision , Paris, France ; CNRS, UMR_7210 , Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Lechauve
authors.affiliation: INSERM, U968 , Paris, France ; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la, Vision , Paris, France ; CNRS, UMR_7210 , Paris, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ayache
authors.affiliation: INSERM, U968 , Paris, France ; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la, Vision , Paris, France ; CNRS, UMR_7210 , Paris, France.
authors.forename: Sami
authors.initials: S
authors.lastname: Ellouze
authors.affiliation: INSERM, U968 , Paris, France ; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la, Vision , Paris, France ; CNRS, UMR_7210 , Paris, France.
authors.forename: José-Alain
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: INSERM, U968 , Paris, France ; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la, Vision , Paris, France ; CNRS, UMR_7210 , Paris, France.
authors.forename: Marisol
authors.initials: M
authors.lastname: Corral-Debrinski