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Journal of Ophthalmology
Volume 2011, Article ID 179412, 16 pages
http://dx.doi.org/10.1155/2011/179412
Review Article

Leber's Hereditary Optic Neuropathy-Gene Therapy: From Benchtop to Bedside

1Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
2McKnight Vision Research Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA

Received 30 June 2010; Revised 7 October 2010; Accepted 12 November 2010

Academic Editor: Radha Ayyagari

Copyright © 2011 Rajeshwari D. Koilkonda and John Guy. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. T. Leber, “Ueber hereditaere und congenital angelegte sehnervenleiden,” Graefes Arch Ophthalmol, vol. 17, pp. 249–291, 1871. View at Google Scholar
  2. N. J. Newman, “Hereditary optic neuropathies: from the mitochondria to the optic nerve,” American Journal of Ophthalmology, vol. 140, no. 3, pp. 517.e1–517.e9, 2005. View at Publisher · View at Google Scholar · View at Scopus
  3. E. Nikoskelainen, W. F. Hoyt, and K. Nummelin, “Ophthalmoscopic findings in Leber's hereditary optic neuropathy. II. The fundus findings in the affected family members,” Archives of Ophthalmology, vol. 101, no. 7, pp. 1059–1068, 1983. View at Google Scholar · View at Scopus
  4. D. C. Wallace, “A new manifestation of Leber's disease and a new explanation for the agency responsible for its unusual pattern of inheritance,” Brain, vol. 93, no. 1, pp. 121–132, 1970. View at Google Scholar · View at Scopus
  5. R. P. Erickson, “Leber's optic atrophy, a possible example of maternal inheritance,” American Journal of Human Genetics, vol. 24, no. 3, pp. 348–349, 1972. View at Google Scholar · View at Scopus
  6. D. C. Wallace, G. Singh, M. T. Lott et al., “Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy,” Science, vol. 242, no. 4884, pp. 1427–1430, 1988. View at Google Scholar · View at Scopus
  7. P. Riordan-Eva, M. D. Sanders, G. G. Govan, M. G. Sweeney, J. Da Costa, and A. E. Harding, “The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation,” Brain, vol. 118, no. 2, pp. 319–337, 1995. View at Google Scholar · View at Scopus
  8. R. M. Chalmers and A. E. Harding, “A case-control study of Leber's hereditary optic neuropathy,” Brain, vol. 119, no. 5, pp. 1481–1486, 1996. View at Publisher · View at Google Scholar · View at Scopus
  9. F. M. Meire, R. Van Coster, P. Cochaux, B. Obermaier-Kusser, C. Candaele, and J. J. Martin, “Neurological disorders in members of families with Leber's hereditary optic neuropathy (LHON) caused by different mitochondrial mutations,” Ophthalmic Genetics, vol. 16, no. 3, pp. 119–126, 1995. View at Google Scholar · View at Scopus
  10. E. K. Nikoskelainen, R. J. Marttila, K. Huoponen et al., “Leber's 'plus': neurological abnormalities in patients with Leber's hereditary optic neuropathy,” Journal of Neurology Neurosurgery and Psychiatry, vol. 59, no. 2, pp. 160–164, 1995. View at Google Scholar · View at Scopus
  11. S. P. C. Bower, I. Hawley, and D. A. Mackey, “Cardiac arrhythmia and Leber's hereditory optic neuropathy,” Lancet, vol. 339, no. 8806, pp. 1427–1428, 1992. View at Google Scholar · View at Scopus
  12. Y. Mashima, K. Kigasawa, H. Hasegawa, M. Tani, and Y. Oguchi, “High incidence of pre-excitation syndrome in Japanese families with Leber's hereditary optic neuropathy,” Clinical Genetics, vol. 50, no. 6, pp. 535–537, 1996. View at Google Scholar · View at Scopus
  13. E. K. Nikoskelainen, M. L. Savontaus, K. Huoponen, K. Antila, and J. Hartiala, “Pre-excitation syndrome in Leber's hereditary optic neuropathy,” Lancet, vol. 344, no. 8926, pp. 857–858, 1994. View at Publisher · View at Google Scholar · View at Scopus
  14. V. Carelli, F. N. Ross-Cisneros, and A. A. Sadun, “Mitochondrial dysfunction as a cause of optic neuropathies,” Progress in Retinal and Eye Research, vol. 23, no. 1, pp. 53–89, 2004. View at Publisher · View at Google Scholar · View at Scopus
  15. A. A. Sadun, P. H. Win, F. N. Ross-Cisneros et al., “Leber's hereditary optic neuropathy differentially affects smaller axons in the optic nerve,” Transactions of the American Ophthalmological Society, vol. 98, pp. 223–235, 2000. View at Google Scholar · View at Scopus
  16. P. Y. W. Man, P. G. Griffiths, D. T. Brown, N. Howell, D. M. Turnbull, and P. F. Chinnery, “The epidemiology of Leber hereditary optic neuropathy in the North East of England,” American Journal of Human Genetics, vol. 72, no. 2, pp. 333–339, 2003. View at Publisher · View at Google Scholar · View at Scopus
  17. A. Puomila, P. Hämäläinen, S. Kivioja et al., “Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland,” European Journal of Human Genetics, vol. 15, no. 10, pp. 1079–1089, 2007. View at Publisher · View at Google Scholar · View at Scopus
  18. D. A. Mackey and R. G. Buttery, “Leber hereditary optic neuropathy in Australia,” Australian and New Zealand Journal of Ophthalmology, vol. 20, no. 3, pp. 177–184, 1992. View at Google Scholar · View at Scopus
  19. W. M. Carroll and F. L. Mastaglia, “Leber's optic neuropathy: a clinical and visual evoked potential study of affected and asymptomatic members of a six generation family,” Brain, vol. 102, no. 3, pp. 559–580, 1979. View at Google Scholar · View at Scopus
  20. N. J. Newman, “Leber's hereditary optic neuropathy: new genetic considerations,” Archives of Neurology, vol. 50, no. 5, pp. 540–548, 1993. View at Google Scholar · View at Scopus
  21. D. R. Johns, K. L. Heber, N. R. Miller, and K. H. Smith, “Leber's hereditary optic neuropathy: clinical manifestations of the 14484 mutation,” Archives of Ophthalmology, vol. 111, no. 4, pp. 495–498, 1993. View at Google Scholar · View at Scopus
  22. J. Palace, “Multiple sclerosis associated with Leber's Hereditary Optic Neuropathy,” Journal of the Neurological Sciences, vol. 286, no. 1-2, pp. 24–27, 2009. View at Publisher · View at Google Scholar · View at Scopus
  23. T. Murakami, S. Mita, M. Tokunaga et al., “Hereditary cerebellar ataxia with Leber's hereditary optic neuropathy mitochondrial DNA 11778 mutation,” Journal of the Neurological Sciences, vol. 142, no. 1-2, pp. 111–113, 1996. View at Publisher · View at Google Scholar · View at Scopus
  24. A. Gropman, T. J. Chen, C. L. Perng et al., “Variable clinical manifestation of homoplasmic G14459A mitochondrial DNA mutation,” American Journal of Medical Genetics, vol. 124, no. 4, pp. 377–382, 2004. View at Google Scholar · View at Scopus
  25. K. K. Abu-Amero, T. M. Bosley, S. Bohlega, and D. McLean, “Complex I respiratory defect in LHON plus dystonia with no mitochondrial DNA mutation,” British Journal of Ophthalmology, vol. 89, no. 10, pp. 1380–1381, 2005. View at Publisher · View at Google Scholar · View at Scopus
  26. J. B. Kerrison, N. R. Miller, F. C. Hsu et al., “A case-control study of tobacco and alcohol consumption in leber hereditary optic neuropathy,” American Journal of Ophthalmology, vol. 130, no. 6, pp. 803–812, 2000. View at Publisher · View at Google Scholar · View at Scopus
  27. N. J. Newman, “Leber hereditary optic neuropathy: bad habits, bad vision,” Brain, vol. 132, no. 9, pp. 2306–2308, 2009. View at Publisher · View at Google Scholar · View at Scopus
  28. M. A. Kirkman, P. Yu-Wai-Man, A. Korsten et al., “Gene-environment interactions in Leber hereditary optic neuropathy,” Brain, vol. 132, no. 9, pp. 2317–2326, 2009. View at Publisher · View at Google Scholar · View at Scopus
  29. U. Lachmund and D. S. Mojon, “Leber's hereditary optic neuropathy in malnutrition: a case report,” Klinische Monatsblatter fur Augenheilkunde, vol. 223, no. 5, pp. 393–396, 2006. View at Publisher · View at Google Scholar · View at Scopus
  30. K. Huoponen, J. Vilkki, P. Aula, E. K. Nikoskelainen, and M. L. Savontaus, “A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy,” American Journal of Human Genetics, vol. 48, no. 6, pp. 1147–1153, 1991. View at Google Scholar · View at Scopus
  31. N. Howell, L. A. Bindoff, D. A. McCullough et al., “Leber hereditary optic neuropathy: identification of the same mitochondrial NDI mutation in six pedigrees,” American Journal of Human Genetics, vol. 49, no. 5, pp. 939–950, 1991. View at Google Scholar · View at Scopus
  32. D. R. Johns, M. J. Neufeld, and R. D. Park, “An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy,” Biochemical and Biophysical Research Communications, vol. 187, no. 3, pp. 1551–1557, 1992. View at Publisher · View at Google Scholar · View at Scopus
  33. D. A. Mackey, R. J. Oostra, T. Rosenberg et al., “Primary pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic neuropathy,” American Journal of Human Genetics, vol. 59, no. 2, pp. 481–485, 1996. View at Google Scholar · View at Scopus
  34. D. Mackey and N. Howell, “A variant of Leber hereditary optic neuropathy characterized by recovery of vision and by an unusual mitochondrial genetic etiology,” American Journal of Human Genetics, vol. 51, no. 6, pp. 1218–1228, 1992. View at Google Scholar · View at Scopus
  35. K. Huoponen, “Leber hereditary optic neuropathy: clinical and molecular genetic findings,” Neurogenetics, vol. 3, no. 3, pp. 119–125, 2001. View at Publisher · View at Google Scholar · View at Scopus
  36. X. Bu and J. I. Rotter, “X chromosome-linked and mitochondrial gene control of Leber hereditary optic neuropathy: evidence from segregation analysis for dependence on X chromosome inactivation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 18, pp. 8198–8202, 1991. View at Google Scholar · View at Scopus
  37. M. D. Brown, F. Sun, and D. C. Wallace, “Clustering of Caucasian Leber hereditary optic neuropathy patients containing the 11778 or 14484 mutations on an mtDNA lineage,” American Journal of Human Genetics, vol. 60, no. 2, pp. 381–387, 1997. View at Google Scholar · View at Scopus
  38. A. Torroni, M. Petrozzi, L. D'Urbano et al., “Haplotype and phylogenetic analyses suggest that one European-specific mtDNA background plays a role in the expression of Leber hereditary optic neuropathy by increasing the penetrance of the primary mutations 11778 and 14484,” American Journal of Human Genetics, vol. 60, no. 5, pp. 1107–1121, 1997. View at Google Scholar · View at Scopus
  39. P. Y. Man, N. Howell, D. A. Mackey et al., “Mitochondrial DNA haplogroup distribution within Leber hereditary optic neuropathy pedigrees,” Journal of Medical Genetics, vol. 41, no. 4, article e41, 2004. View at Google Scholar · View at Scopus
  40. V. Carelli, A. Achilli, M. L. Valentino et al., “Haplogroup effects and recombination of mitochondrial DNA: novel clues from the analysis of leber hereditary optic neuropathy pedigrees,” American Journal of Human Genetics, vol. 78, no. 4, pp. 564–574, 2006. View at Publisher · View at Google Scholar · View at Scopus
  41. N. Howell, C. Herrnstadt, C. Shults, and D. A. Mackey, “Low penetrance of the 14484 LHON mutation when it arises in a non-haplogroup J mtDNA background,” American Journal of Medical Genetics, vol. 119, no. 2, pp. 147–151, 2003. View at Google Scholar · View at Scopus
  42. L. Vergani, A. Martinuzzi, V. Carelli et al., “MtDNA mutations associated with Leber's hereditary optic neuropathy: studies on cytoplasmic hybrid (cybrid) cells,” Biochemical and Biophysical Research Communications, vol. 210, no. 3, pp. 880–888, 1995. View at Publisher · View at Google Scholar · View at Scopus
  43. V. Carelli, L. Vergani, B. Bernazzi et al., “Respiratory function in cybrid cell lines carrying European mtDNA haplogroups: implications for Leber's hereditary optic neuropathy,” Biochimica et Biophysica Acta - Molecular Basis of Disease, vol. 1588, no. 1, pp. 7–14, 2002. View at Publisher · View at Google Scholar · View at Scopus
  44. R. Pello, M. A. Martín, V. Carelli et al., “Mitochondrial DNA background modulates the assembly kinetics of OXPHOS complexes in a cellular model of mitochondrial disease,” Human Molecular Genetics, vol. 17, no. 24, pp. 4001–4011, 2008. View at Publisher · View at Google Scholar · View at Scopus
  45. A. M. Ghelli, A. M. Porcelli, C. Zanna et al., “The background of mitochondrial DNA haplogroup J increases the sensitivity of Leber's hereditary optic neuropathy cells to 2,5-hexanedione toxicity,” PLoS One, vol. 4, no. 11, Article ID e7922, 2009. View at Publisher · View at Google Scholar · View at Scopus
  46. P. Yu-Wai-Man, P. G. Griffiths, G. Hudson, and P. F. Chinnery, “Inherited mitochondrial optic neuropathies,” Journal of Medical Genetics, vol. 46, no. 3, pp. 145–158, 2009. View at Publisher · View at Google Scholar · View at Scopus
  47. B. Lemire, “Mitochondrial genetics,” WormBook, pp. 1–10, 2005. View at Google Scholar · View at Scopus
  48. K. H. Smith, D. R. Johns, K. L. Heher, and N. R. Miller, “Heteroplasmy in Leber's hereditary optic neuropathy,” Archives of Ophthalmology, vol. 111, no. 11, pp. 1486–1490, 1993. View at Google Scholar · View at Scopus
  49. F. K. Jacobi, B. Leo-Kottler, K. Mittelviefhaus et al., “Segregation patterns and heteroplasmy prevalence in Leber's hereditary optic neuropathy,” Investigative Ophthalmology and Visual Science, vol. 42, no. 6, pp. 1208–1214, 2001. View at Google Scholar · View at Scopus
  50. N. Phasukkijwatana, W. L. Chuenkongkaew, R. Suphavilai, K. Luangtrakool, B. Kunhapan, and P. Lertrit, “Transmission of heteroplasmic G11778A in extensive pedigrees of Thai Leber hereditary optic neuropathy,” Journal of Human Genetics, vol. 51, no. 12, pp. 1110–1117, 2006. View at Publisher · View at Google Scholar · View at Scopus
  51. N. Phasukkijwatana, W. L. Chuenkongkaew, R. Suphavilai et al., “The unique characteristics of Thai Leber hereditary optic neuropathy: analysis of 30 G11778A pedigrees,” Journal of Human Genetics, vol. 51, no. 4, pp. 298–304, 2006. View at Publisher · View at Google Scholar · View at Scopus
  52. M. T. Lott, A. S. Voljavec, and D. C. Wallace, “Variable genotype of Leber's hereditary optic neuropathy patients,” American Journal of Ophthalmology, vol. 109, no. 6, pp. 625–631, 1990. View at Google Scholar · View at Scopus
  53. P. A. Bolhuis, E. M. Bleeker-Wagemakers, N. J. Ponne et al., “Rapid shift in genotype of human mitochondrial DNA in a family with Leber's hereditary optic neuropathy,” Biochemical and Biophysical Research Communications, vol. 170, no. 3, pp. 994–997, 1990. View at Publisher · View at Google Scholar · View at Scopus
  54. N. Howell, M. Xu, S. Halvorson, I. Bodis-Wollner, and J. Sherman, “A heteroplasmic LHON family: tissue distribution and transmission of the 11778 mutation,” American Journal of Human Genetics, vol. 55, no. 1, pp. 203–206, 1994. View at Google Scholar · View at Scopus
  55. R. N. Lightowlers, P. F. Chinnery, D. M. Turnbull, and N. Howell, “Mammalian mitochondrial genetics: heredity, heteroplasmy and disease,” Trends in Genetics, vol. 13, no. 11, pp. 450–455, 1997. View at Publisher · View at Google Scholar · View at Scopus
  56. M. Y. Yen, T. C. Yen, C. Y. Pang, J. H. Liu, and Y. H. Wei, “Mitochondrial DNA mutation in Leber's hereditary optic neuropathy,” Investigative Ophthalmology and Visual Science, vol. 33, no. 8, pp. 2561–2566, 1992. View at Google Scholar · View at Scopus
  57. P. Barboni, V. Mantovani, P. Montagna et al., “Mitochondrial DNA analysis in Leber's hereditary optic neuropathy,” Ophthalmic Paediatrics and Genetics, vol. 13, no. 4, pp. 219–226, 1992. View at Google Scholar · View at Scopus
  58. A. Puomila, T. Viitanen, M. L. Savontaus, E. Nikoskelainen, and K. Huoponen, “Segregation of the ND4/11778 and the ND1/3460 mutations in four heteroplasmic LHON families,” Journal of the Neurological Sciences, vol. 205, no. 1, pp. 41–45, 2002. View at Publisher · View at Google Scholar · View at Scopus
  59. M. Y. Yen, AN. G. Wang, and Y. H. Wei, “Leber's hereditary optic neuropathy: a multifactorial disease,” Progress in Retinal and Eye Research, vol. 25, no. 4, pp. 381–396, 2006. View at Publisher · View at Google Scholar · View at Scopus
  60. W. L. Chuenkongkaew, R. Suphavilai, L. Vaeusorn, N. Phasukkijwatana, P. Lertrit, and B. Suktitipat, “Proportion of 11778 mutant mitochondrial DNA and clinical expression in a Thai population with Leber hereditary optic neuropathy,” Journal of Neuro-Ophthalmology, vol. 25, no. 3, pp. 173–175, 2005. View at Publisher · View at Google Scholar · View at Scopus
  61. P. F. Chinnery, R. M. Andrews, D. M. Turnbull, and N. Howell, “Leber hereditary optic neuropathy: does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation?” American Journal of Medical Genetics, vol. 98, no. 3, pp. 235–243, 2001. View at Publisher · View at Google Scholar · View at Scopus
  62. S. T. Brady, R. J. Lasek, and R. D. Allen, “Video microscopy of fast axonal transport in extruded axoplasm: a new model for study of molecular mechanisms,” Cell Motility, vol. 5, no. 2, pp. 81–101, 1985. View at Google Scholar · View at Scopus
  63. V. Carelli, F. N. Ross-Cisneros, and A. A. Sadun, “Optic nerve degeneration and mitochondrial dysfunction: genetic and acquired optic neuropathies,” Neurochemistry International, vol. 40, no. 6, pp. 573–584, 2002. View at Publisher · View at Google Scholar · View at Scopus
  64. A. Wong and G. Cortopassi, “mtDNA mutations confer cellular sensitivity to oxidant stress that is partially rescued by calcium depletion and cyclosporin A,” Biochemical and Biophysical Research Communications, vol. 239, no. 1, pp. 139–145, 1997. View at Publisher · View at Google Scholar · View at Scopus
  65. C. Zanna, A. Ghelli, A. M. Porcelli, A. Martinuzzi, V. Carelli, and M. Rugolo, “Caspase-independent death of Leber's hereditary optic neuropathy cybrids is driven by energetic failure and mediated by AIF and Endonuclease G,” Apoptosis, vol. 10, no. 5, pp. 997–1007, 2005. View at Publisher · View at Google Scholar · View at Scopus
  66. C. Zanna, A. Ghelli, A. M. Porcelli, V. Carelli, A. Martinuzzi, and M. Rugolo, “Apoptotic cell death of cybrid cells bearing Leber's hereditary optic neuropathy mutations is caspase independent,” Annals of the New York Academy of Sciences, vol. 1010, pp. 213–217, 2003. View at Publisher · View at Google Scholar · View at Scopus
  67. C. Battisti, P. Formichi, E. Cardaioli et al., “Cell response to oxidative stress incluced apoptosis in patients with Leber's hereditary optic neuropathy,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 75, no. 12, pp. 1731–1736, 2004. View at Publisher · View at Google Scholar · View at Scopus
  68. S. Beretta, L. Mattavelli, G. Sala et al., “Leber hereditary optic neuropathy mtDNA mutations disrupt glutamate transport in cybrid cell lines,” Brain, vol. 127, no. 10, pp. 2183–2192, 2004. View at Publisher · View at Google Scholar · View at Scopus
  69. L. A. Levin, “Mechanisms of retinal ganglion specific-cell death in Leber hereditary optic neuropathy,” Transactions of the American Ophthalmological Society, vol. 105, pp. 379–391, 2007. View at Google Scholar · View at Scopus
  70. S. R. Danielson, A. Wong, V. Carelli, A. Martinuzzi, A. H. V. Schapira, and G. A. Cortopassi, “Cells bearing mutations causing Leber's hereditary optic neuropathy are sensitized to Fas-induced apoptosis,” Journal of Biological Chemistry, vol. 277, no. 8, pp. 5810–5815, 2002. View at Publisher · View at Google Scholar · View at Scopus
  71. P. Cortelli, P. Montagna, G. Pierangeli et al., “Clinical and brain bioenergetics improvement with idebenone in a patient with Leber's hereditary optic neuropathy: a clinical and 31P-MRS study,” Journal of the Neurological Sciences, vol. 148, no. 1, pp. 25–31, 1997. View at Google Scholar
  72. V. Carelli, P. Barboni, A. Zacchini et al., “Leber's hereditary optic neuropathy (LHON) with 14484/ND6 mutation in a North African patient,” Journal of the Neurological Sciences, vol. 160, no. 2, pp. 183–188, 1998. View at Publisher · View at Google Scholar · View at Scopus
  73. Y. Mashima, K. Kigasawa, M. Wakakura, and Y. Oguchi, “Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy?” Journal of Neuro-Ophthalmology, vol. 20, no. 3, pp. 166–170, 2000. View at Google Scholar · View at Scopus
  74. N. Barnils García, E. Mesa, S. Muñoz, A. Ferrer-Artola, and J. Arruga, “Response to idebenone and multivitamin therapy in Leber's hereditary optic neuropathy,” Archivos de la Sociedad Espanola de Oftalmologia, vol. 82, no. 6, pp. 377–380, 2007. View at Google Scholar · View at Scopus
  75. N. J. Newman, V. Biousse, R. David et al., “Prophylaxis for second eye involvement in leber hereditary optic neuropathy: an open-labeled, nonrandomized multicenter trial of topical brimonidine purite,” American Journal of Ophthalmology, vol. 140, no. 3, pp. 407.e1–407.e11, 2005. View at Publisher · View at Google Scholar · View at Scopus
  76. G. Manfredi and M. F. Beal, “Poison and antidote: a novel model to study pathogenesis and therapy of LHON,” Annals of Neurology, vol. 56, no. 2, pp. 171–172, 2004. View at Publisher · View at Google Scholar · View at Scopus
  77. X. Zhang, D. Jones, and F. Gonzalez-Lima, “Mouse model of optic neuropathy caused by mitochondrial complex I dysfunction,” Neuroscience Letters, vol. 326, no. 2, pp. 97–100, 2002. View at Publisher · View at Google Scholar · View at Scopus
  78. X. Qi, A. S. Lewin, W. W. Hauswirth, and J. Guy, “Suppression of complex I gene expression induces optic neuropathy,” Annals of Neurology, vol. 53, no. 2, pp. 198–205, 2003. View at Publisher · View at Google Scholar · View at Scopus
  79. X. Qi, A. S. Lewin, W. W. Hauswirth, and J. Guy, “Optic neuropathy induced by reductions in mitochondrial superoxide dismutase,” Investigative Ophthalmology and Visual Science, vol. 44, no. 3, pp. 1088–1096, 2003. View at Publisher · View at Google Scholar · View at Scopus
  80. X. Qi, A. S. Lewin, L. Sun, W. W. Hauswirth, and J. Guy, “SOD2 gene transfer protects against optic neuropathy induced by deficiency of complex I,” Annals of Neurology, vol. 56, no. 2, pp. 182–191, 2004. View at Publisher · View at Google Scholar · View at Scopus
  81. X. Qi, L. Sun, W. W. Hauswirth, A. S. Lewin, and J. Guy, “Use of mitochondrial antioxidant defenses for rescue of cells with a leber hereditary optic neuropathy-causing mutation,” Archives of Ophthalmology, vol. 125, no. 2, pp. 268–272, 2007. View at Publisher · View at Google Scholar · View at Scopus
  82. A. Kanamori, M.-M. Catrinescu, N. Kanamori, K. A. Mears, R. Beaubien, and L. A. Levin, “Superoxide is an associated signal for apoptosis in axonal injury,” Brain, vol. 133, no. 9, pp. 2612–2625, 2010. View at Publisher · View at Google Scholar
  83. X. Qi, L. Sun, A. S. Lewin, W. W. Hauswirth, and J. Guy, “The mutant human ND4 subunit of complex I induces optic neuropathy in the mouse,” Investigative Ophthalmology and Visual Science, vol. 48, no. 1, pp. 1–10, 2007. View at Publisher · View at Google Scholar · View at Scopus
  84. S. Ellouze, S. Augustin, A. Bouaita et al., “Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction,” American Journal of Human Genetics, vol. 83, no. 3, pp. 373–387, 2008. View at Publisher · View at Google Scholar · View at Scopus
  85. N. G. Larsson, “Leber hereditary optic neuropathy: a nuclear solution of a mitochondrial problem,” Annals of Neurology, vol. 52, no. 5, pp. 529–530, 2002. View at Publisher · View at Google Scholar · View at Scopus
  86. J. Guy, X. Qi, F. Pallotti et al., “Rescue of a mitochondrial deficiency causing Leber Hereditary Optic Neuropathy,” Annals of Neurology, vol. 52, no. 5, pp. 534–542, 2002. View at Publisher · View at Google Scholar · View at Scopus
  87. J. Guy, X. Qi, R. D. Koilkonda et al., “Efficiency and safety of AAV-mediated gene delivery of the human ND4 complex I subunit in the mouse visual system,” Investigative Ophthalmology & Visual Science, vol. 50, no. 9, pp. 4205–4214, 2009. View at Google Scholar · View at Scopus
  88. T. Tsukihara, K. Shimokata, Y. Katayama et al., “The low-spin heme of cytochrome c oxidase as the driving element of the proton-pumping process,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 26, pp. 15304–15309, 2003. View at Publisher · View at Google Scholar · View at Scopus
  89. F. Figueroa-Martínez, M. Vázquez-Acevedo, P. Cortés-Hernández et al., “What limits the allotopic expression of nucleus-encoded mitochondrial genes? The case of the chimeric Cox3 and Atp6 genes,” Mitochondrion. In press. View at Publisher · View at Google Scholar
  90. P. S. Brookes, A. Pinner, A. Ramachandran et al., “High throughput two-dimensional blue-native electrophoresis: a tool for functional proteomics of mitochondria and signaling complexes,” Proteomics, vol. 2, no. 8, pp. 969–977, 2002. View at Publisher · View at Google Scholar · View at Scopus
  91. J. Oca-Cossio, L. Kenyon, H. Hao, and C. T. Moraes, “Limitations of allotopic expression of mitochondrial genes in mammalian cells,” Genetics, vol. 165, no. 2, pp. 707–720, 2003. View at Google Scholar
  92. R. W. Gilkerson, J. M. L. Selker, and R. A. Capaldi, “The cristal membrane of mitochondria is the principal site of oxidative phosphorylation,” FEBS Letters, vol. 546, no. 2-3, pp. 355–358, 2003. View at Publisher · View at Google Scholar · View at Scopus
  93. L. Supekova, F. Supek, J. E. Greer, and P. G. Schultz, “A single mutation in the first transmembrane domain of yeast COX2 enables its allotopic expression,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 11, pp. 5047–5052, 2010. View at Publisher · View at Google Scholar · View at Scopus
  94. C. Bonnet, V. Kaltimbacher, S. Ellouze et al., “Allotopic mRNA localization to the mitochondrial surface rescues respiratory chain defects in fibroblasts harboring mitochondrial DNA mutations affecting complex I or V subunits,” Rejuvenation Research, vol. 10, no. 2, pp. 127–143, 2007. View at Publisher · View at Google Scholar · View at Scopus
  95. I. N. Shokolenko, M. F. Alexeyev, S. P. Ledoux, and G. L. Wilson, “The approaches for manipulating mitochondrial proteome,” Environmental and Molecular Mutagenesis, vol. 51, no. 5, pp. 451–461, 2010. View at Publisher · View at Google Scholar · View at Scopus
  96. E. Perales-Clemente, P. Fernandez-Silva, R. Acin-Perez, A. Perez-Martos, and J. A. Enriquez, “Allotopic expression of mitochondrial-encoded genes in mammals: achieved goal, undemonstrated mechanism or impossible task?” Nucleic Acids Research. In press.
  97. W. W. Hauswirth, T. S. Aleman, S. Kaushal et al., “Treatment of Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial,” Human Gene Therapy, vol. 19, no. 10, pp. 979–990, 2008. View at Publisher · View at Google Scholar · View at Scopus
  98. B. B. Seo, E. Nakamaru-Ogiso, T. R. Flotte, A. Matsuno-Yagi, and T. Yagi, “In vivo complementation of complex I by the yeast Ndi1 enzyme: possible application for treatment of Parkinson disease,” Journal of Biological Chemistry, vol. 281, no. 20, pp. 14250–14255, 2006. View at Publisher · View at Google Scholar · View at Scopus
  99. L. Dudus, V. Anand, G. M. Acland et al., “Persistent transgene product in retina, optic nerve and brain after intraocular injection of rAAV,” Vision Research, vol. 39, no. 15, pp. 2545–2553, 1999. View at Publisher · View at Google Scholar
  100. J. Guy, X. Qi, N. Muzyczka, and W. W. Hauswirth, “Reporter expression persists 1 year after adeno-associated virus- mediated gene transfer to the optic nerve,” Archives of Ophthalmology, vol. 117, no. 7, pp. 929–937, 1999. View at Google Scholar · View at Scopus
  101. G. M. Acland, G. D. Aguirre, J. Ray et al., “Gene therapy restores vision in a canine model of childhood blindness,” Nature Genetics, vol. 28, no. 1, pp. 92–95, 2001. View at Publisher · View at Google Scholar · View at Scopus
  102. D. M. McCarty, “Self-complementary AAV vectors; advances and applications,” Molecular Therapy, vol. 16, no. 10, pp. 1648–1656, 2008. View at Publisher · View at Google Scholar · View at Scopus
  103. D. M. McCarty, P. E. Monahan, and R. J. Samulski, “Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis,” Gene Therapy, vol. 8, no. 16, pp. 1248–1254, 2001. View at Publisher · View at Google Scholar · View at Scopus
  104. D. M. McCarty, H. Fu, P. E. Monahan, C. E. Toulson, P. Naik, and R. J. Samulski, “Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo,” Gene Therapy, vol. 10, no. 26, pp. 2112–2118, 2003. View at Publisher · View at Google Scholar · View at Scopus
  105. LI. Zhong, B. Li, G. Jayandharan et al., “Tyrosine-phosphorylation of AAV2 vectors and its consequences on viral intracellular trafficking and transgene expression,” Virology, vol. 381, no. 2, pp. 194–202, 2008. View at Publisher · View at Google Scholar · View at Scopus
  106. LI. Zhong, B. Li, C. S. Mah et al., “Next generation of adeno-associated virus 2 vectors: point mutations in tyrosines lead to high-efficiency transduction at lower doses,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 22, pp. 7827–7832, 2008. View at Publisher · View at Google Scholar · View at Scopus
  107. R. D. Koilkonda, T.-H. Chou, V. Porciatti, W. W. Hauswirth, and J. Guy, “Induction of rapid and highly efficient expression of the human ND4 complex I subunit in the mouse visual system by self-complementary adeno-associated virus,” Archives of Ophthalmology, vol. 128, no. 7, pp. 876–883, 2010. View at Publisher · View at Google Scholar
  108. A. K. Zaiss and D. A. Muruve, “Immunity to adeno-associated virus vectors in animals and humans: a continued challenge,” Gene Therapy, vol. 15, no. 11, pp. 808–816, 2008. View at Publisher · View at Google Scholar · View at Scopus
  109. M. Tachibana, M. Sparman, H. Sritanaudomchai et al., “Mitochondrial gene replacement in primate offspring and embryonic stem cells,” Nature, vol. 461, no. 7262, pp. 367–372, 2009. View at Publisher · View at Google Scholar · View at Scopus
  110. P. M. Keeney, C. K. Quigley, L. D. Dunham et al., “Mitochondrial gene therapy augments mitochondrial physiology in a Parkinson's disease cell model,” Human Gene Therapy, vol. 20, no. 8, pp. 897–907, 2009. View at Publisher · View at Google Scholar · View at Scopus
  111. S. R. Bacman, S. L. Williams, D. Hernandez, and C. T. Moraes, “Modulating mtDNA heteroplasmy by mitochondria-targeted restriction endonucleases in a 'differential multiple cleavage-site' model,” Gene Therapy, vol. 14, no. 18, pp. 1309–1318, 2007. View at Publisher · View at Google Scholar · View at Scopus
  112. S. DiMauro, M. Hirano, and E. A. Schon, “Approaches to the treatment of mitochondrial diseases,” Muscle and Nerve, vol. 34, no. 3, pp. 265–283, 2006. View at Publisher · View at Google Scholar · View at Scopus
  113. M. P. Bayona-Bafaluy, B. Blits, B. J. Battersby, E. A. Shoubridge, and C. T. Moraes, “Rapid directional shift of mitochondrial DNA heteroplasmy in animal tissues by a mitochondrially targeted restriction endonuclease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 40, pp. 14392–14397, 2005. View at Publisher · View at Google Scholar · View at Scopus
  114. J. Ojaimi, J. Pan, S. Santra, W. J. Snell, and E. A. Schon, “An algal nucleus-encoded subunit of mitochondrial ATP synthase rescues a defect in the analogous human mitochondrial-encoded subunit,” Molecular Biology of the Cell, vol. 13, no. 11, pp. 3836–3844, 2002. View at Publisher · View at Google Scholar · View at Scopus
  115. B. B. Seo, T. Kitajima-Ihara, E. K. L. Chan, I. E. Scheffler, A. Matsuno-Yagi, and T. Yagi, “Molecular remedy of complex I defects: rotenone-insensitive internal NADH-quinone oxidoreductase of Saccharomyces cerevisiae mitochondria restores the NADH oxidase activity of complex I-deficient mammalian cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 16, pp. 9167–9171, 1998. View at Google Scholar · View at Scopus
  116. Y. Bai, P. Hájek, A. Chomyn et al., “Lack of complex I activity in human cells carrying a mutation in MtDNA-encoded ND4 subunit is corrected by the Saccharomyces cerevisiae NADH-quinone oxidoreductase (NDI1) gene,” Journal of Biological Chemistry, vol. 276, no. 42, pp. 38808–38813, 2001. View at Publisher · View at Google Scholar · View at Scopus
  117. M. Marella, B. B. Seo, B. B. Thomas, A. Matsuno-Yagi, and T. Yagi, “Successful amelioration of mitochondrial optic neuropathy using the yeast NDI1 gene in a rat animal model,” PLoS One, vol. 5, no. 7, Article ID e11472, 2010. View at Publisher · View at Google Scholar
  118. S. Bahadorani, J. Cho, T. Lo et al., “Neuronal expression of a single-subunit yeast NADH-ubiquinone oxidoreductase (Ndi1) extends Drosophila lifespan,” Aging cell, vol. 9, no. 2, pp. 191–202, 2010. View at Google Scholar · View at Scopus
  119. B. L. Lam, W. J. Feuer, F. Abukhalil, V. Porciatti, W. W. Hauswirth, and J. Guy, “Leber hereditary optic neuropathy gene therapy clinical trial recruitment: year 1,” Archives of Ophthalmology, vol. 128, no. 9, pp. 1129–1135, 2010. View at Publisher · View at Google Scholar
  120. J. W. B. Bainbridge, “Prospects for gene therapy of inherited retinal disease,” Eye, vol. 23, no. 10, pp. 1898–1903, 2009. View at Publisher · View at Google Scholar · View at Scopus
  121. A. M. Maguire, F. Simonelli, E. A. Pierce et al., “Safety and efficacy of gene transfer for Leber's congenital amaurosis,” New England Journal of Medicine, vol. 358, no. 21, pp. 2240–2248, 2008. View at Publisher · View at Google Scholar · View at Scopus
  122. M. Matsumoto, S. Hayasaka, C. Kadoi et al., “Secondary mutations of mitochondrial DNA in Japanese patients with Leber's hereditary optic neuropathy,” Ophthalmic Genetics, vol. 20, no. 3, pp. 153–160, 1999. View at Google Scholar · View at Scopus
  123. E. L. Blakely, R. de Silva, A. King et al., “LHON/MELAS overlap syndrome associated with a mitochondrial MTND1 gene mutation,” European Journal of Human Genetics, vol. 13, no. 5, pp. 623–627, 2005. View at Publisher · View at Google Scholar · View at Scopus
  124. M. D. Brown, A. S. Voljavec, M. T. Lott, A. Torroni, C. C. Yang, and D. C. Wallace, “Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy,” Genetics, vol. 130, no. 1, pp. 163–173, 1992. View at Google Scholar · View at Scopus
  125. M. D. Brown, S. Zhadanov, J. C. Allen et al., “Novel mtDNA mutations and oxidative phosphorylation dysfunction in Russian LHON families,” Human Genetics, vol. 109, no. 1, pp. 33–39, 2001. View at Publisher · View at Google Scholar · View at Scopus
  126. S. Fauser, J. Luberichs, D. Besch, and B. Leo-Kottler, “Sequence analysis of the complete mitochondrial genome in patients with Leber's hereditary optic neuropathy lacking the three most common pathogenic DNA mutations,” Biochemical and Biophysical Research Communications, vol. 295, no. 2, pp. 342–347, 2002. View at Publisher · View at Google Scholar · View at Scopus
  127. M. L. Valentino, P. Barboni, A. Ghelli et al., “The ND1 gene of complex I is a mutational hot spot for Leber's hereditary optic neuropathy,” Annals of Neurology, vol. 56, no. 5, pp. 631–641, 2004. View at Publisher · View at Google Scholar · View at Scopus
  128. K. Huoponen, T. Lamminen, V. Juvonen, P. Aula, E. Nikoskelainen, and M. L. Savontaus, “The spectrum of mitochondrial DNA mutations in families with Leber hereditary optic neuroretinopathy,” Human Genetics, vol. 92, no. 4, pp. 379–384, 1993. View at Publisher · View at Google Scholar · View at Scopus
  129. N. Howell, I. Kubacka, M. Xu, and D. A. McCullough, “Leber hereditary optic neuropathy: involvement of the mitochondrial ND1 gene and evidence for an intragenic suppressor mutation,” American Journal of Human Genetics, vol. 48, no. 5, pp. 935–942, 1991. View at Google Scholar · View at Scopus
  130. J. Y. Kim, J. M. Hwang, and S. S. Park, “Mitochondrial DNA C4171A/ND1 is a novel primary causative mutation of Leber's hereditary optic neuropathy with a good prognosis,” Annals of Neurology, vol. 51, no. 5, pp. 630–634, 2002. View at Publisher · View at Google Scholar
  131. D. R. Johns and J. Berman, “Alternative, simultaneous complex I mitochondrial DNA mutations in Leber's hereditary optic neuropathy,” Biochemical and Biophysical Research Communications, vol. 174, no. 3, pp. 1324–1330, 1991. View at Google Scholar · View at Scopus
  132. K. K. Abu-Amero and T. M. Bosley, “Mitochondrial abnormalities in patients with LHON-like optic neuropathies,” Investigative Ophthalmology and Visual Science, vol. 47, no. 10, pp. 4211–4220, 2006. View at Publisher · View at Google Scholar · View at Scopus
  133. M. D. Brown, C.-C. Yang, I. Trounce, A. Torroni, M. T. Lott, and D. C. Wallace, “A mitochondrial DNA variant, identified in Leber hereditary optic neuropathy patients, which extends the amino acid sequence of cytochrome c oxidase subunit I,” American Journal of Human Genetics, vol. 51, no. 2, pp. 378–385, 1992. View at Google Scholar
  134. J. Yang, Y. Zhu, YI. Tong et al., “The novel G10680A mutation is associated with complete penetrance of the LHON/T14484C family,” Mitochondrion, vol. 9, no. 4, pp. 273–278, 2009. View at Publisher · View at Google Scholar · View at Scopus
  135. M. D. Brown, A. S. Voljavec, M. T. Lott, I. MacDonald, and D. C. Wallace, “Leber's hereditary optic neuropathy: a model for mitochondrial neurodegenerative diseases,” FASEB Journal, vol. 6, no. 10, pp. 2791–2799, 1992. View at Google Scholar · View at Scopus
  136. J. Horvath, R. Horvath, V. Karcagi, S. Komoly, and D. R. Johns, “Sequence analysis of Hungarian LHON patients not carrying the common primary mutations,” Journal of Inherited Metabolic Disease, vol. 25, no. 4, pp. 323–324, 2002. View at Publisher · View at Google Scholar · View at Scopus
  137. P. Kjer, “Infantile optic atrophy with dominant mode of inheritance: a clinical and genetic study of 19 Danish families,” Acta Ophthalmologica. Supplement, vol. 164, supplement 54, pp. 1–147, 1959. View at Google Scholar
  138. D. D. De Vries, L. N. Went, G. W. Bruyn et al., “Genetic and biochemical impairment of mitochondrial complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia,” American Journal of Human Genetics, vol. 58, no. 4, pp. 703–711, 1996. View at Google Scholar · View at Scopus
  139. M. D. Brown, A. Torroni, C. L. Reckord, and D. C. Wallace, “Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent occurrences of the common mutations,” Human Mutation, vol. 6, no. 4, pp. 311–325, 1995. View at Publisher · View at Google Scholar · View at Scopus
  140. V. Mayorov, V. Biousse, N. J. Newman, and M. D. Brown, “The role of the ND5 gene in LHON: characterization of a new, heteroplasmic LHON mutation,” Annals of Neurology, vol. 58, no. 5, pp. 807–811, 2005. View at Publisher · View at Google Scholar · View at Scopus
  141. D. Liolitsa, S. Rahman, S. Benton, L. J. Carr, and M. G. Hanna, “Is the mitochondrial complex I ND5 gene a hot-spot for MELAS causing mutations?” Annals of Neurology, vol. 53, no. 1, pp. 128–132, 2003. View at Publisher · View at Google Scholar · View at Scopus
  142. N. Howell, R. J. Oostra, P. A. Bolhuis et al., “Sequence analysis of the mitochondrial genomes from Dutch pedigrees with leber hereditary optic neuropathy,” American Journal of Human Genetics, vol. 72, no. 6, pp. 1460–1469, 2003. View at Publisher · View at Google Scholar · View at Scopus
  143. C. Batandier, A. Picard, N. Tessier, and J. Lunardi, “Identification of a novel T398A mutation in the ND5 subunit of the mitochondrial complex I and of three novel mtDNA polymorphisms in two patients presenting ocular symptoms,” Human Mutation, vol. 16, no. 6, p. 532, 2000. View at Google Scholar · View at Scopus
  144. N. Howell, S. Halvorson, J. Burns, D. A. McCullough, and J. Poulton, “When does bilateral optic atrophy become Leber hereditary optic neuropathy?” American Journal of Human Genetics, vol. 53, no. 4, pp. 959–963, 1993. View at Google Scholar · View at Scopus
  145. D. Besch, B. Leo-Kottler, E. Zrenner, and B. Wissinger, “Leber's hereditary optic neuropathy: clinical and molecular genetic findings in a patient with a new mutation in the ND6 gene,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 237, no. 9, pp. 745–752, 1999. View at Publisher · View at Google Scholar · View at Scopus
  146. S. I. Zhadanov, V. V. Atamanov, N. I. Zhadanov, O. V. Oleinikov, L. P. Osipova, and T. G. Schurr, “A novel mtDNA ND6 gene mutation associated with LHON in a Caucasian family,” Biochemical and Biophysical Research Communications, vol. 332, no. 4, pp. 1115–1121, 2005. View at Publisher · View at Google Scholar · View at Scopus
  147. A. S. Jun, M. D. Brown, and D. C. Wallace, “A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber hereditary optic neuropathy and dystonia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 13, pp. 6206–6210, 1994. View at Publisher · View at Google Scholar · View at Scopus
  148. N. Howell, C. Bogolin, R. Jamieson, D. R. Marenda, and D. A. Mackey, “mtDNA mutations that cause optic neuropathy: how do we know?” American Journal of Human Genetics, vol. 62, no. 1, pp. 196–202, 1998. View at Publisher · View at Google Scholar · View at Scopus
  149. P. F. Chinnery, D. T. Brown, R. M. Andrews et al., “The mitochondrial ND6 gene is a hot spot for mutations that cause Leber's hereditary optic neuropathy,” Brain, vol. 124, no. 1, pp. 209–218, 2001. View at Google Scholar · View at Scopus
  150. B. Wissinger, D. Besch, B. Baumann et al., “Mutation analysis of the ND6 gene in patients with lebers hereditary optic neuropathy,” Biochemical and Biophysical Research Communications, vol. 234, no. 2, pp. 511–515, 1997. View at Publisher · View at Google Scholar · View at Scopus
  151. C. La. Morgia, A. Achilli, L. Iommarini et al., “Rare mtDNA variants in Leber hereditary optic neuropathy families with recurrence of myoclonus,” Neurology, vol. 70, no. 10, pp. 762–770, 2008. View at Publisher · View at Google Scholar · View at Scopus
  152. D. R. Johns and M. J. Neufeld, “Cytochrome b mutations in Leber hereditary optic neuropathy,” Biochemical and Biophysical Research Communications, vol. 181, no. 3, pp. 1358–1364, 1991. View at Google Scholar · View at Scopus
  153. D. R. Johns and M. J. Neufeld, “Cytochrome c oxidase mutations in Leber hereditary optic neuropathy,” Biochemical and Biophysical Research Communications, vol. 196, no. 2, pp. 810–815, 1993. View at Publisher · View at Google Scholar · View at Scopus
  154. N. Povalko, E. Zakharova, G. Rudenskaia et al., “A new sequence variant in mitochondrial DNA associated with high penetrance of Russian Leber hereditary optic neuropathy,” Mitochondrion, vol. 5, no. 3, pp. 194–199, 2005. View at Publisher · View at Google Scholar · View at Scopus