Statement of the DOG, the RG, and the BVA on the therapeutic use of voretigene neparvovec (Luxturna™) in ophthalmology. English version

January 2019
  • German Society of Ophthalmology (Deutsche Ophthalmologische Gesellschaft, DOG)Email author
  • German Retina Society e. V. (Retinologische Gesellschaft e. V., RG)
  • Professional Association of German Ophthalmologists (Berufsverband der Augenärzte Deutschlands e. V., BVA)
Leitlinien, Stellungnahmen und Empfehlungen

Luxturna™ was approved in the European Union for the treatment of retinal dystrophy in patients with biallelic RPE65 mutations and sufficient viable retinal cells on 23 November 2018. The following article presents the treatment recommendations for Luxturna™ (Novartis, Basel, Switzerland) formulated on the basis of a consensus between the German Retina Society, the German Ophthalmological Society, and the German Professional Association of Ophthalmologists.

1 Key messages of the statement

All of the following conditions should be met prior to performing treatment with Luxturna™:
  • The diagnosis of retinal dystrophy has been clinically confirmed. Grade of recommendation: ⇑⇑

  • Biallelic (homozygous or compound heterozygous) sequence variants in the RPE65 gene have been identified as the cause of disease. Ideally, identification is performed by means of segregation analysis in the parents. Grade of recommendation: ⇑⇑

  • It has been established that sufficient target cells are available to ensure...

Stellungnahme von DOG, RG und BVA zur therapeutischen Anwendung von voretigene neparvovec (Luxturna™) in der Augenheilkunde. Englische Version

Stand Januar 2019


Editorial board

Prof. Dr. med. Dominik Fischer, Tübingen, Germany (lead editor)

Prof. Dr. med. Bernd Bertram, Aachen, Germany

Prof. Dr. med. Ulrich, Kellner, Siegburg, Germany

Prof. Dr. med. Hansjuergen Agostini, Freiburg im Breisgau, Germany

Prof. Dr. med. Birgit Lorenz, Giessen, Germany

Dr. med. Philipp Herrmann, Bonn, Germany

Compliance with ethical guidelines

Conflict of interest

See Table 2 in the appendix.

This article does not contain any studies with human participants or animals performed by any of the authors.

The supplement containing this article is not sponsored by industry.


  1. 1.
    Russell S, Bennett J, Wellman JA, Chung DC, Yu ZF, Tillman A, Wittes J, Pappas J, Elci O, McCague S, Cross D, Marshall KA, Walshire J, Kehoe TL, Reichert H, Davis M, Raffini L, George LA, Hudson FP, Dingfield L, Zhu X, Haller JA, Sohn EH, Mahajan VB, Pfeifer W, Weckmann M, Johnson C, Gewaily D, Drack A, Stone E, Wachtel K, Simonelli F, Leroy BP, Wright JF, High KA, Maguire AM (2017) Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet 390:849–860. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Bellingrath JS, Fischer MD (2015) Gene therapy as a treatment concept for inherited retinal diseases. Ophthalmologe 112:720–727. CrossRefPubMedGoogle Scholar
  3. 3.
    Fischer MD (2016) On retinal gene therapy. Ophthalmologica 236:1–7. CrossRefPubMedGoogle Scholar
  4. 4.
    Thompson DA, Gyurus P, Fleischer LL, Bingham EL, McHenry CL, Apfelstedt-Sylla E, Zrenner E, Lorenz B, Richards JE, Jacobson SG, Sieving PA, Gal A (2000) Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration. Invest Ophthalmol Vis Sci 41:4293–4299PubMedGoogle Scholar
  5. 5.
    Chung DC, Bertelsen M, Lorenz B, Pennesi ME, Leroy BP, Hamel CP, Pierce E, Sallum J, Larsen M, Stieger K, Preising M, Weleber R, Yang P, Place E, Liu E, Schaefer G, DiStefano-Pappas J, Elci OU, McCague S, Wellman JA, High KA, Reape KZ (2018) The natural history of inherited retinal dystrophy due to biallelic mutations in the RPE65 gene. Am J Ophthalmol. CrossRefPubMedGoogle Scholar
  6. 6.
    Lorenz B, Gyurus P, Preising M, Bremser D, Gu S, Andrassi M, Gerth C, Gal A (2000) Early-onset severe rod-cone dystrophy in young children with RPE65 mutations. Invest Ophthalmol Vis Sci 41:2735–2742PubMedGoogle Scholar
  7. 7.
    Lorenz B, Poliakov E, Schambeck M, Friedburg C, Preising MN, Redmond TM (2008) A comprehensive clinical and biochemical functional study of a novel RPE65 hypomorphic mutation. Invest Ophthalmol Vis Sci 49:5235–5242. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Narfstrom K, Vaegan KM, Bragadottir R, Rakoczy EP, Seeliger M (2005) Assessment of structure and function over a 3-year period after gene transfer in RPE65-/- dogs. Doc Ophthalmol 111:39–48. CrossRefPubMedGoogle Scholar
  9. 9.
    Maguire AM, High KA, Auricchio A, Wright JF, Pierce EA, Testa F, Mingozzi F, Bennicelli JL, Ying GS, Rossi S, Fulton A, Marshall KA, Banfi S, Chung DC, Morgan JI, Hauck B, Zelenaia O, Zhu X, Raffini L, Coppieters F, De Baere E, Shindler KS, Volpe NJ, Surace EM, Acerra C, Lyubarsky A, Redmond TM, Stone E, Sun J, McDonnell JW, Leroy BP, Simonelli F, Bennett J (2009) Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial. Lancet 374:1597–1605. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr., Mingozzi F, Bennicelli J, Banfi S, Marshall KA, Testa F, Surace EM, Rossi S, Lyubarsky A, Arruda VR, Konkle B, Stone E, Sun J, Jacobs J, Dell’Osso L, Hertle R, Ma JX, Redmond TM, Zhu X, Hauck B, Zelenaia O, Shindler KS, Maguire MG, Wright JF, Volpe NJ, McDonnell JW, Auricchio A, High KA, Bennett J (2008) Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 358:2240–2248. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Cideciyan AV, Jacobson SG, Beltran WA, Sumaroka A, Swider M, Iwabe S, Roman AJ, Olivares MB, Schwartz SB, Komaromy AM, Hauswirth WW, Aguirre GD (2013) Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc Natl Acad Sci U S A. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, Stockman A, Tyler N, Petersen-Jones S, Bhattacharya SS, Thrasher AJ, Fitzke FW, Carter BJ, Rubin GS, Moore AT, Ali RR (2008) Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med 358:2231–2239. CrossRefPubMedGoogle Scholar
  13. 13.
    Stieger K, Lorenz B (2018) Gentherapie bei degenerativen Erkrankungen der Netzhaut – ein Update. Z Prakt Augenheilkd 39:241–254Google Scholar
  14. 14.
    Nelles M, Stieger K, Preising MN, Kruse J, Lorenz B (2015) Shared decision-making, control preferences and psychological well-being in patients with RPE65 deficiency awaiting experimental gene therapy. Ophthalmic Res 54:96–102. CrossRefPubMedGoogle Scholar
  15. 15.
    Lorenz B, Wabbels B, Wegscheider E, Hamel CP, Drexler W, Preising MN (2004) Lack of fundus autofluorescence to 488 nanometers from childhood on in patients with early-onset severe retinal dystrophy associated with mutations in RPE65. Ophthalmology 111:1585–1594. CrossRefPubMedGoogle Scholar
  16. 16.
    Paunescu K, Wabbels B, Preising MN, Lorenz B (2005) Longitudinal and cross-sectional study of patients with early-onset severe retinal dystrophy associated with RPE65 mutations. Graefes Arch Clin Exp Ophthalmol 243:417–426. CrossRefPubMedGoogle Scholar
  17. 17.
    Robson AG, Nilsson J, Li S, Jalali S, Fulton AB, Tormene AP, Holder GE, Brodie SE (2018) ISCEV guide to visual electrodiagnostic procedures. Doc Ophthalmol 136:1–26. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Kumaran N, Pennesi ME, Yang P, Trzupek KM, Schlechter C, Moore AT, Weleber RG, Michaelides M (1993) Leber congenital amaurosis / early-onset severe retinal dystrophy overview. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds) GeneReviews((R)). University of Washington, SeattleGoogle Scholar
  19. 19.
    Jacobson SG, Aleman TS, Cideciyan AV, Heon E, Golczak M, Beltran WA, Sumaroka A, Schwartz SB, Roman AJ, Windsor EA, Wilson JM, Aguirre GD, Stone EM, Palczewski K (2007) Human cone photoreceptor dependence on RPE65 isomerase. Proc Natl Acad Sci U S A 104:15123–15128. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Lorenz B, Strohmayr E, Zahn S, Friedburg C, Kramer M, Preising M, Stieger K (2012) Chromatic pupillometry dissects function of the three different light-sensitive retinal cell populations in RPE65 deficiency. Invest Ophthalmol Vis Sci 53:5641–5652. CrossRefPubMedGoogle Scholar
  21. 21.
    Roman AJ, Schwartz SB, Aleman TS, Cideciyan AV, Chico JD, Windsor EA, Gardner LM, Ying GS, Smilko EE, Maguire MG, Jacobson SG (2005) Quantifying rod photoreceptor-mediated vision in retinal degenerations: dark-adapted thresholds as outcome measures. Exp Eye Res 80:259–272. CrossRefPubMedGoogle Scholar
  22. 22.
    Roman AJ, Cideciyan AV, Aleman TS, Jacobson SG (2007) Full-field stimulus testing (FST) to quantify visual perception in severely blind candidates for treatment trials. Physiol Meas 28:N51–N56. CrossRefPubMedGoogle Scholar
  23. 23.
    Jacobson SG, Aleman TS, Cideciyan AV, Roman AJ, Sumaroka A, Windsor EA, Schwartz SB, Heon E, Stone EM (2009) Defining the residual vision in leber congenital amaurosis caused by RPE65 mutations. Invest Ophthalmol Vis Sci 50:2368–2375. CrossRefPubMedGoogle Scholar
  24. 24.
    Gu SM, Thompson DA, Srikumari CR, Lorenz B, Finckh U, Nicoletti A, Murthy KR, Rathmann M, Kumaramanickavel G, Denton MJ, Gal A (1997) Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy. Nat Genet 17:194–197. CrossRefPubMedGoogle Scholar
  25. 25.
    Fischer MD, Hickey DG, Singh MS, MacLaren RE (2016) Evaluation of an optimized injection system for retinal gene therapy in human patients. Hum Gene Ther Methods 27:150–158. CrossRefPubMedGoogle Scholar
  26. 26.
    Seitz IP, Michalakis S, Wilhelm B, Reichel FF, Ochakovski GA, Zrenner E, Ueffing M, Biel M, Wissinger B, Bartz-Schmidt KU, Peters T, Fischer MD, RDCC (2017) Superior retinal gene transfer and biodistribution profile of subretinal versus Intravitreal delivery of AAV8 in nonhuman primates. Invest Ophthalmol Vis Sci 58:5792–5801. CrossRefPubMedGoogle Scholar
  27. 27.
    Reichel FF, Peters T, Wilhelm B, Biel M, Ueffing M, Wissinger B, Bartz-Schmidt KU, Klein R, Michalakis S, Fischer MD, Consortium R‑C (2018) Humoral immune response after intravitreal but not after subretinal AAV8 in primates and patients. Invest Ophthalmol Vis Sci 59:1910–1915. CrossRefPubMedGoogle Scholar
  28. 28.
    Bennett J, Ashtari M, Wellman J, Marshall KA, Cyckowski LL, Chung DC, McCague S, Pierce EA, Chen Y, Bennicelli JL, Zhu X, Ying GS, Sun J, Wright JF, Auricchio A, Simonelli F, Shindler KS, Mingozzi F, High KA, Maguire AM (2012) AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med 4:120ra115. CrossRefGoogle Scholar
  29. 29.
    Willett K, Bennett J (2013) Immunology of AAV-mediated gene transfer in the eye. Front Immunol 4:261. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Testa F, Maguire AM, Rossi S, Pierce EA, Melillo P, Marshall K, Banfi S, Surace EM, Sun J, Acerra C, Wright JF, Wellman J, High KA, Auricchio A, Bennett J, Simonelli F (2013) Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital Amaurosis type 2. Ophthalmology 120:1283–1291. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Ashtari M, Zhang H, Cook PA, Cyckowski LL, Shindler KS, Marshall KA, Aravand P, Vossough A, Gee JC, Maguire AM, Baker CI, Bennett J (2015) Plasticity of the human visual system after retinal gene therapy in patients with Leber’s congenital amaurosis. Sci Transl Med 7:296ra110. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Jacobson SG, Cideciyan AV, Roman AJ, Sumaroka A, Schwartz SB, Heon E, Hauswirth WW (2015) Improvement and decline in vision with gene therapy in childhood blindness. N Engl J Med 372:1920–1926. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2019

Authors and Affiliations

  • German Society of Ophthalmology (Deutsche Ophthalmologische Gesellschaft, DOG)
    • 1
    Email author
  • German Retina Society e. V. (Retinologische Gesellschaft e. V., RG)
    • 2
  • Professional Association of German Ophthalmologists (Berufsverband der Augenärzte Deutschlands e. V., BVA)
    • 3
  1. 1.German Society of Ophthalmology (Deutsche Ophthalmologische Gesellschaft)MunichGermany
  2. 2.German Retina Society (Retinologische Gesellschaft e. V.)FreiburgGermany
  3. 3.Professional Association of German Ophthalmologists (Berufsverband der Augenärzte Deutschlands e. V.)DüsseldorfGermany

Personalised recommendations