Advertisement

Treatment of Leber Hereditary Optic Neuropathy

  • Patrick Yu-Wai-Man
  • Byron L. Lam
Chapter

Abstract

Leber hereditary optic neuropathy (LHON) is a primary mitochondrial DNA (mtDNA) disorder characterised by bilateral, painless, subacute, central visual loss. The majority of patients harbour one of three mtDNA point mutations (m.3460G>A, m.11778G>A and m.14484T>C) with the m.11778G>A mutation being the most common cause of LHON worldwide. This mitochondrial optic neuropathy is characterised by the preferential early loss of retinal ganglion cells (RGCs) within the papillomacular bundle, which accounts for the dense central or caecocentral scotoma observed in this disorder. The management of LHON remains largely supportive, but rapid advances in drug discovery and genetic engineering are paving the way for more targeted strategies aimed at rescuing RGCs and improving the visual prognosis. Although a number of ethical and scientific concerns have been raised that need to be addressed further, mitochondrial replacement therapy offers the hope of preventing the maternal transmission of mtDNA LHON mutations for female carriers of childbearing age who wish to have their own biological children.

Keywords

Gene therapy Idebenone Leber hereditary optic neuropathy Mitochondrial donation Neuroprotection Retinal ganglion cell 

Notes

Acknowledgments

PYWM is supported by a Clinician Scientist Fellowship Award (G1002570) from the Medical Research Council (UK), and also receives funding from Fight for Sight (UK), the Isaac Newton Trust (UK), the UK National Institute of Health Research (NIHR) as part of the Rare Diseases Translational Research Collaboration, and the NIHR Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. BLL is supported in part by a National Eye Institute grant (U10 EY023558-01A1) and by the Robert Z. and Nancy J. Greene Chair in Ophthalmology, Bascom Palmer Eye Institute, University of Miami. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

Conflicts of Interest

PYWM holds a consultancy agreement with GenSight Biologics (Paris, France).

References

  1. 1.
    Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies – disease mechanisms and therapeutic strategies. Prog Retin Eye Res. 2011;30:81–114.CrossRefGoogle Scholar
  2. 2.
    Yu-Wai-Man P, Votruba M, Burte F, La Morgia C, Barboni P, Carelli V. A neurodegenerative perspective on mitochondrial optic neuropathies. Acta Neuropathol. 2016;132:789–806.CrossRefGoogle Scholar
  3. 3.
    Fraser JA, Biousse V, Newman NJ. The neuro-ophthalmology of mitochondrial disease. Surv Ophthalmol. 2010;55:299–334.CrossRefGoogle Scholar
  4. 4.
    Kirkman MA, Korsten A, Leonhardt M, Dimitriadis K, De Coo IF, Klopstock T, Griffiths PG, Hudson G, Chinnery PF, Yu-Wai-Man P. Quality of life in patients with Leber hereditary optic neuropathy. Invest Ophthalmol Vis Sci. 2009;50:3112–5.CrossRefGoogle Scholar
  5. 5.
    Pfeffer G, Majamaa K, Turnbull DM, Thorburn D, Chinnery PF. Treatment for mitochondrial disorders. Cochrane Database Syst Rev. 2012;4:CD004426.Google Scholar
  6. 6.
    Yu-Wai-Man P, Votruba M, Moore AT, Chinnery PF. Treatment strategies for inherited optic neuropathies: past, present and future. Eye. 2014;28:521–37.CrossRefGoogle Scholar
  7. 7.
    Yu-Wai-Man P, Soiferman D, Moore DG, Burte F, Saada A. Evaluating the therapeutic potential of idebenone and related quinone analogues in Leber hereditary optic neuropathy. Mitochondrion. 2017;36:36–42.CrossRefGoogle Scholar
  8. 8.
    Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, Atawan A, Chattopadhyay S, Schubert M, Garip A, et al. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain. 2011;134:2677–86.CrossRefGoogle Scholar
  9. 9.
    Carelli V, La Morgia C, Valentino ML, Rizzo G, Carbonelli M, De Negri AM, Sadun F, Carta A, Guerriero S, Simonelli F, et al. Idebenone treatment in Leber's hereditary optic neuropathy. Brain. 2011;134:e188.CrossRefGoogle Scholar
  10. 10.
    Carelli V, Carbonelli M, de Coo IF, Kawasaki A, Klopstock T, Lagreze WA, La Morgia C, Newman NJ, Orssaud C, Pott JWR, et al. International consensus statement on the clinical and therapeutic management of leber hereditary optic neuropathy. J Neuroophthalmol. 2017;37:371–81.CrossRefGoogle Scholar
  11. 11.
    Sadun AA, Chicani CF, Ross-Cisneros FN, Barboni P, Thoolen M, Shrader WD, Kubis K, Carelli V, Miller G. Effect of EPI-743 on the clinical course of the mitochondrial disease Leber hereditary optic neuropathy. Arch Neurol. 2012;69:331–8.CrossRefGoogle Scholar
  12. 12.
    Karaa A, Haas R, Goldstein A, Vockley J, Weaver WD, Cohen BH. Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy. Neurology. 2018;90:e1212–21.CrossRefGoogle Scholar
  13. 13.
    Giordano C, Montopoli M, Perli E, Orlandi M, Fantin M, Ross-Cisneros FN, Caparrotta L, Martinuzzi A, Ragazzi E, Ghelli A, et al. Oestrogens ameliorate mitochondrial dysfunction in Leber’s hereditary optic neuropathy. Brain. 2011;134:220–34.CrossRefGoogle Scholar
  14. 14.
    Pisano A, Preziuso C, Iommarini L, Perli E, Grazioli P, Campese AF, Maresca A, Montopoli M, Masuelli L, Sadun AA, et al. Targeting estrogen receptor beta as preventive therapeutic strategy for Leber’s hereditary optic neuropathy. Hum Mol Genet. 2015;24:6921–31.PubMedGoogle Scholar
  15. 15.
    Pfeffer G, Horvath R, Klopstock T, Mootha VK, Suomalainen A, Koene S, Hirano M, Zeviani M, Bindoff LA, Yu-Wai-Man P, et al. New treatments for mitochondrial disease-no time to drop our standards. Nat Rev Neurol. 2013;9:474–81.CrossRefGoogle Scholar
  16. 16.
    Jurkute N, Yu-Wai-Man P. Leber hereditary optic neuropathy: bridging the translational gap. Curr Opin Ophthalmol. 2017;28:403–9.CrossRefGoogle Scholar
  17. 17.
    Yu-Wai-Man P. Harnessing the power of genetic engineering for patients with mitochondrial eye diseases. J Neuroophthalmol. 2017;37:56–64.CrossRefGoogle Scholar
  18. 18.
    Guy J, Qi XP, Pallotti F, Schon EA, Manfredi G, Carelli V, Martinuzzi A, Hauswirth WW, Lewin AS. Rescue of a mitochondrial deficiency causing Leber hereditary optic neuropathy. Ann Neurol. 2002;52:534–42.CrossRefGoogle Scholar
  19. 19.
    Ellouze S, Augustin S, Bouaita A, Bonnet C, Simonutti M, Forster V, Picaud S, Sahel JA, 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;83:373–87.CrossRefGoogle Scholar
  20. 20.
    Wan X, Pei H, Zhao MJ, Yang S, Hu WK, He H, Ma SQ, Zhang G, Dong XY, Chen C, et al. Efficacy and safety of rAAV2-ND4 treatment for Leber’s hereditary optic neuropathy. Sci Rep. 2016;6:21587.CrossRefGoogle Scholar
  21. 21.
    Guy J, Feuer WJ, Davis JL, Porciatti V, Gonzalez PJ, Koilkonda RD, Yuan HJ, Hauswirth WW, Lam BL. Gene therapy for Leber hereditary optic neuropathy. Ophthalmology. 2017;124:1621–34.CrossRefGoogle Scholar
  22. 22.
    Vignal C, Uretsky S, Fitoussi S, Galy A, Blouin L, Girmens JF, Bidot S, Thomasson N, Bouquet C, Valero S, et al. Safety of rAAV2/2-ND4 gene therapy for Leber hereditary optic neuropathy. Ophthalmology. 2018;125:945–7.CrossRefGoogle Scholar
  23. 23.
    Hyslop LA, Blakeley P, Craven L, Richardson J, Fogarty NME, Fragouli E, Lamb M, Wamaitha SE, Prathalingam N, Zhang Q, et al. Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease. Nature. 2016;534:383–6.CrossRefGoogle Scholar
  24. 24.
    Kang EJ, Wu J, Gutierrez NM, Koski A, Tippner-Hedges R, Agaronyan K, Platero-Luengo A, Martinez-Redondo P, Ma H, Lee Y, et al. Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations. Nature. 2016;540:270–5.CrossRefGoogle Scholar
  25. 25.
    Herbert M, Turnbull D. Mitochondrial donation – clearing the final regulatory hurdle in the United Kingdom. N Engl J Med. 2017;376:171–3.CrossRefGoogle Scholar
  26. 26.
    Chinnery PF, Zeviani M. Mitochondrial matchmaking. N Engl J Med. 2016;375:1894–6.CrossRefGoogle Scholar
  27. 27.
    Zhang J, Liu H, Luo S, Lu Z, Chavez-Badiola A, Liu Z, Yang M, Merhi Z, Silber SJ, Munne S, et al. Live birth derived from oocyte spindle transfer to prevent mitochondrial disease. Reprod Biomed Online. 2017;34:361–8.CrossRefGoogle Scholar
  28. 28.
    Alikani M, Fauser BC, Garcia-Valesco JA, Simpson JL, Johnson MH. First birth following spindle transfer for mitochondrial replacement therapy: hope and trepidation. Reprod Biomed Online. 2017;34:333–6.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of OphthalmologyLondonUK
  2. 2.Cambridge Eye Unit, Addenbrooke’s HospitalCambridge University HospitalsCambridgeUK
  3. 3.MRC Mitochondrial Biology UnitUniversity of CambridgeCambridgeUK
  4. 4.Department of Clinical Neurosciences, Cambridge Centre for Brain RepairUniversity of CambridgeCambridgeUK
  5. 5.Bascom Palmer Eye InstituteUniversity of MiamiMiamiUSA

Personalised recommendations