Adeno-Associated Virus (AAV)-Mediated Gene Therapy for Leber Hereditary Optic Neuropathy

  • Kunpeng Xie
  • Shuai Ming
  • Mingzhu Yang
  • Xuemin Jin
  • Bo Lei
Part of the Essentials in Ophthalmology book series (ESSENTIALS)


Leber hereditary optic neuropathy (LHON) is the first clinically characterized maternally inherited mitochondrial disorder. Up to now, more than 30 pathogenic point mutations in mitochondrial DNA (mtDNA) coding for the respiratory chain subunits of complex I genes, which are highly susceptible to disrupted ATP production and oxidative stress, have been identified to cause LHON. The fundamental cell type affected in LHON is the retinal ganglion cells. Many researches facilitated the progress of animal models in vivo and cell culture in vitro that have been used to determine the effects of the genetic mutations upon the clinical phenotype and to explore potential novel therapies. More recently, clinical studies applying gene therapy have shown promising results in treating LHON. This article reviewed the efficacy and safety of recombinant adeno-associated virus 2 carrying ND4 (rAAV2-ND4) in clinical trials and its allotopic expression in the LHON patients with the G11778A mutation, which accounts for the majority of this vision-threatening disorder.


Leber hereditary optic neuropathy Allotopic expression AAV2-ND4 Gene therapy Retinal ganglion cell 



This study is supported by the National Natural Science Foundation of China grants (81470621, 81770949), National Key Clinical Specialties Construction Program of China, Henan Science and Technology Bureau (182102310145), Henan Provincial Clinical Research Center, and Henan Key Laboratory of Ophthalmology and Visual Science. The authors alone are responsible for the content and writing of the paper.

Compliance with Ethical Requirements

The authors have no conflict of interest to declare.


  1. 1.
    Wallace D, Singh G, Lott M, Hodge J, Schurr T, Lezza A, Elsas L, Nikoskelainen E. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science. 1988;242(4884):1427–30.CrossRefGoogle Scholar
  2. 2.
    Yen M-Y, Wang A-G, Wei Y-H. Leber’s hereditary optic neuropathy: a multifactorial disease. Prog Retin Eye Res. 2006;25(4):381–96.CrossRefGoogle Scholar
  3. 3.
    Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies–disease mechanisms and therapeutic strategies. Prog Retin Eye Res. 2011;30(2):81–114.CrossRefGoogle Scholar
  4. 4.
    Man P, Griffiths P, Brown D, Howell N, Turnbull D, Chinnery P. The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum Genet. 2003;72(2):333–9.CrossRefGoogle Scholar
  5. 5.
    Spruijt L, Kolbach DN, Rene F, Plomp AS, Bauer NJ, Smeets HJ, de Die-Smulders CE. Influence of mutation type on clinical expression of Leber hereditary optic neuropathy. Am J ophthalmol. 2006;141(4):676–8.CrossRefGoogle Scholar
  6. 6.
    Puomila A, Hämäläinen P, Kivioja S, Savontaus M-L, Koivumäki S, Huoponen K, Nikoskelainen E. Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland. Eur J Hum Genet: EJHG. 2007;15(10):1079.CrossRefGoogle Scholar
  7. 7.
    Riordan-Eva P, Sanders M, Govan G, Sweeney M, Costa JD, Harding A. The clinical features of Leber’s hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain. 1995;118(2):319–37.CrossRefGoogle Scholar
  8. 8.
    Sadun AA, La Morgia C, Carelli V. Leber’s hereditary optic neuropathy. Curr Treat Options Neurol. 2011;13(1):109–17.CrossRefGoogle Scholar
  9. 9.
    Lyseng-Williamson KA. Idebenone: a review in Leber’s hereditary optic neuropathy. Drugs. 2016;76(7):805–13.CrossRefGoogle Scholar
  10. 10.
    Ochakovski GA, Bartz-Schmidt KU, Fischer MD. Retinal gene therapy: surgical vector delivery in the translation to clinical trials. Front Neurosci. 2017;11:174.CrossRefGoogle Scholar
  11. 11.
    Willett K, Bennett J. Immunology of AAV-mediated gene transfer in the eye. Front Immunol. 2013;4:261.CrossRefGoogle Scholar
  12. 12.
    Carelli V, La Morgia C, Valentino ML, Barboni P, Ross-Cisneros FN, Sadun AA. Retinal ganglion cell neurodegeneration in mitochondrial inherited disorders. Biochim Biophys Acta Bioenergetics. 2009;1787(5):518–28.CrossRefGoogle Scholar
  13. 13.
    Yu-Wai-Man P. Genetic manipulation for inherited neurodegenerative diseases: myth or reality? Br J Ophthalmol. 2016;100(10):1322–31.CrossRefGoogle Scholar
  14. 14.
    Ellouze S, Augustin S, Bouaita A, Bonnet C, Simonutti M, Forster V, Picaud S, Sahel J-A, Corral-Debrinski M. Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction. Am J Hum Genet. 2008;83(3):373–87.CrossRefGoogle Scholar
  15. 15.
    Berns K, Giraud C. Biology of adeno-associated virus. In: Adeno-Associated Virus (AAV) vectors in gene therapy. Berlin: Springer; 1996. p. 1–23.CrossRefGoogle Scholar
  16. 16.
    Sonntag F, Schmidt K, Kleinschmidt JA. A viral assembly factor promotes AAV2 capsid formation in the nucleolus. Proc Natl Acad Sci. 2010;107(22):10220–5.CrossRefGoogle Scholar
  17. 17.
    Daya S, Berns KI. Gene therapy using adeno-associated virus vectors. Clin Microbiol Rev. 2008;21(4):583–93.CrossRefGoogle Scholar
  18. 18.
    Trapani I, Puppo A, Auricchio A. Vector platforms for gene therapy of inherited retinopathies. Prog Retin Eye Res. 2014;43:108–28.CrossRefGoogle Scholar
  19. 19.
    Guy J, Feuer WJ, Davis JL, Porciatti V, Gonzalez PJ, Koilkonda RD, Yuan H, Hauswirth WW, Lam BL. Gene therapy for Leber hereditary optic neuropathy: low-and medium-dose visual results. Ophthalmology. 2017;124(11):1621–34.CrossRefGoogle Scholar
  20. 20.
    Feuer WJ, Schiffman JC, Davis JL, Porciatti V, Gonzalez P, Koilkonda RD, Yuan H, Lalwani A, Lam BL, Guy J. Gene therapy for Leber hereditary optic neuropathy: initial results. Ophthalmology. 2016;123(3):558–70.CrossRefGoogle Scholar
  21. 21.
    Yang S, Ma SQ, Wan X, He H, Pei H, Zhao MJ, Chen C, Wang DW, Dong XY, Yuan JJ. Long-term outcomes of gene therapy for the treatment of Leber’s hereditary optic neuropathy. EBioMedicine. 2016;10:258–68.CrossRefGoogle Scholar
  22. 22.
    Bonnet C, Kaltimbacher V, Ellouze S, Augustin S, Bénit P, Forster V, Rustin P, Sahel J-A, Corral-Debrinski M. Allotopic mRNA localization to the mitochondrial surface rescues respiratory chain defects in fibroblasts harboring mitochondrial DNA mutations affecting complex I or v subunits. Rejuvenation Res. 2007;10(2):127–44.CrossRefGoogle Scholar
  23. 23.
    Wan X, Pei H, Zhao MJ, Yang S, Hu WK, He H, Ma SQ, Zhang G, Dong XY, Chen C. Efficacy and safety of rAAV2-ND4 treatment for Leber’s hereditary optic neuropathy. Sci Rep. 2016;6:srep21587.CrossRefGoogle Scholar
  24. 24.
    Koilkonda RD, Chou T-H, Porciatti V, Hauswirth WW, Guy J. 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. Arch Ophthalmol. 2010;128(7):876–83.CrossRefGoogle Scholar
  25. 25.
    Yang S, He H, Zhu Y, Wan X, Zhou LF, Wang J, Wang WF, Liu L, Li B. Chemical and material communication between the optic nerves in rats. Clin Exp Ophthalmol. 2015;43(8):742–8.CrossRefGoogle Scholar
  26. 26.
    Luo X, Salgueiro Y, Beckerman SR, Lemmon VP, Tsoulfas P, Park KK. Three-dimensional evaluation of retinal ganglion cell axon regeneration and pathfinding in whole mouse tissue after injury. Exp Neurol. 2013;247:653–62.CrossRefGoogle Scholar
  27. 27.
    Barboni P, Savini G, Feuer WJ, Budenz DL, Carbonelli M, Chicani F, Ramos CDV, Salomao SR, Negri AD, Parisi V. Retinal nerve fiber layer thickness variability in Leber hereditary optic neuropathy carriers. Eur J Ophthalmol. 2012;22(6):985–91.CrossRefGoogle Scholar
  28. 28.
    Zhang Y, Huang H, Wei S, Gong Y, Li H, Dai Y, Zhao S, Wang Y, Yan H. Characterization of macular thickness changes in Leber’s hereditary optic neuropathy by optical coherence tomography. BMC Ophthalmol. 2014;14(1):105.CrossRefGoogle Scholar
  29. 29.
    Marella M, Seo BB, Thomas BB, Matsuno-Yagi A, Yagi T. Successful amelioration of mitochondrial optic neuropathy using the yeast NDI1 gene in a rat animal model. PLoS One. 2010;5(7):e11472.CrossRefGoogle Scholar
  30. 30.
    Chadderton N, Palfi A, Millington-Ward S, Gobbo O, Overlack N, Carrigan M, O’reilly M, Campbell M, Ehrhardt C, Wolfrum U. Intravitreal delivery of AAV-NDI1 provides functional benefit in a murine model of Leber hereditary optic neuropathy. Eur J Hum Genet. 2013;21(1):62.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Kunpeng Xie
    • 1
  • Shuai Ming
    • 1
  • Mingzhu Yang
    • 1
  • Xuemin Jin
    • 1
  • Bo Lei
    • 1
  1. 1.Henan Eye Institute, Henan Eye Hospital, Henan Provincial People’s HospitalZhengzhouChina

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