Nuclear expression of mitochondrial ND4 leads to the protein assembling in complex I and prevents optic atrophy and visual loss

• Main Authors: Hélène Cwerman-Thibault, Sébastien Augustin, Christophe Lechauve, Jessica Ayache, Sami Ellouze, José-Alain Sahel, Marisol Corral-Debrinski
• Format: Article
• Language: English
• Published: Elsevier 2015-01-01
• Series: Molecular Therapy: Methods & Clinical Development
• Online Access: http://www.sciencedirect.com/science/article/pii/S2329050116300158

Leber hereditary optic neuropathy is due to mitochondrial DNA mutations; in â¼70% 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.