Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction.
Mitochondrial diseases due to mutations in mitochondrial DNA can no longer be ignored in most medical areas. With prevalence certainly higher than one in 6000, they probably represent the most common form of metabolic disorders. Despite progress in identification of their molecular mechanisms, little has been done with regard to therapy. We have recently optimized the allotopic expression for the mitochondrial genes ATP6, ND1, and ND4 and obtained a complete and long-lasting rescue of mitochondrial dysfunction in the human fibroblasts in which these genes were mutated. However, biosafety and benefit to mitochondrial function must be validated in animal models prior to clinical applications. To create an animal model of Leber Hereditary Optic Neuropathy (LHON), we introduced the human ND4 gene harboring the G11778A mutation, responsible of 60% of LHON cases, to rat eyes by in vivo electroporation. The treatment induced the degeneration of retinal ganglion cells (RGCs), which were 40% less abundant in treated eyes than in control eyes. This deleterious effect was also confirmed in primary cell culture, in which both RGC survival and neurite outgrowth were compromised. Importantly, RGC loss was clearly associated with a decline in visual performance. A subsequent electroporation with wild-type ND4 prevented both RGC loss and the impairment of visual function. Hence, these data provide the proof-of-principle that optimized allotopic expression can be an effective treatment for LHON, and they open the way to clinical studies on other devastating mitochondrial disorders.
Ellouze
Sami
S
Institut de la Vision, Université Pierre et Marie Curie-Paris6, Unité mixte de recherche S 592, 17 rue Moreau, Paris F-75012, France.
Augustin
Sébastien
S
Bouaita
Aicha
A
Bonnet
Crystel
C
Simonutti
Manuel
M
Forster
Valérie
V
Picaud
Serge
S
Sahel
Jose-Alain
JA
Corral-Debrinski
Marisol
M
D000818:Animals; D001766:Blindness / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D009154:Mutation; D009245:NADH Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics*; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D012165:Retinal Ganglion Cells / Q000473:pathology
D004272:DNA, Mitochondrial; C098483:NADH dehydrogenase subunit 4; D009245:NADH Dehydrogenase
Nat Genet. 2002 Apr;30(4):394-9
11925565
Am J Hum Genet. 2003 Feb;72(2):333-9
12518276
Rejuvenation Res. 2007 Jun;10(2):127-44
17518546
Mitochondrion. 2004 Sep;4(5-6):695-703
16120425
Invest Ophthalmol Vis Sci. 2007 Jan;48(1):1-10
17197509
Curr Top Dev Biol. 2007;77:113-55
17222702
Biochim Biophys Acta. 2008 Oct;1783(10):1707-17
18513491
N Engl J Med. 2008 May 22;358(21):2240-8
18441370
RNA. 2006 Jul;12(7):1408-17
16751614
Ann N Y Acad Sci. 2006 May;1067:182-90
16803984
N Engl J Med. 2008 May 22;358(21):2231-9
18441371
Lancet. 2006 Jul 1;368(9529):70-82
16815381
Invest Ophthalmol Vis Sci. 2005 Aug;46(8):2983-91
16043875
Mol Vis. 2004 Feb 10;10:83-92
14961007
Gene Ther. 2006 Aug;13(16):1191-7
16838031
Neurobiol Aging. 2006 Jul;27(7):983-93
15979212
Genetics. 2003 Oct;165(2):707-20
14573482
Biosci Rep. 2007 Jun;27(1-3):125-37
17486439
Ann Neurol. 2008 Jan;63(1):35-9
17886296
Vis Neurosci. 2005 Sep-Oct;22(5):677-84
16332278
Invest Ophthalmol Vis Sci. 2006 Oct;47(10):4211-20
17003408
Gene Ther. 2005 Feb;12(4):289-98
15616607
Trans Am Ophthalmol Soc. 2006;104:51-61
17471325
Prog Retin Eye Res. 2006 Jul;25(4):381-96
16829155
Mol Ther. 2004 Nov;10(5):929-37
15509510
Biosci Rep. 2007 Jun;27(1-3):173-84
17479363
Nat Neurosci. 2002 Jan;5(1):53-6
11753416
Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004426
16437486
Rejuvenation Res. 2006 Winter;9(4):455-69
17105386
Ann Neurol. 2002 Nov;52(5):534-42
12402249
Endocrinology. 2007 May;148(5):2335-44
17255207
Neuron. 1988 Nov;1(9):791-803
2908449
Prog Retin Eye Res. 2004 Jan;23(1):53-89
14766317
Invest Ophthalmol Vis Sci. 2002 Mar;43(3):587-94
11867571
Hum Gene Ther. 2006 Aug;17(8):845-58
16942444
Science. 1988 Dec 9;242(4884):1427-30
3201231
Nucleic Acids Res. 2007 Jan;35(Database issue):D823-8
17178747
Mol Genet Metab. 2005 Sep-Oct;86(1-2):51-60
16194617
J Neurosci. 1995 Jul;15(7 Pt 1):4762-85
7623109
Exp Brain Res. 1979 May 2;35(3):443-55
456452
Adv Exp Med Biol. 2006;572:15-20
17249549
Neuron. 2004 Aug 19;43(4):475-85
15312647