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Development of retinal atrophy after subretinal gene therapy with voretigene neparvovec
  1. Felix Friedrich Reichel,
  2. Immanuel Seitz,
  3. Fabian Wozar,
  4. Spyridon Dimopoulos,
  5. Ronja Jung,
  6. Melanie Kempf,
  7. Susanne Kohl,
  8. Friederike Charlotte Kortüm,
  9. Saskia Ott,
  10. Lisa Pohl,
  11. Krunoslav Stingl,
  12. Karl Ulrich Bartz-Schmidt,
  13. Katarina Stingl,
  14. M. Dominik Fischer
  1. Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany
  1. Correspondence to M. Dominik Fischer, Centre for Ophthalmology, Universitätsklinikum Tübingen Universitäts-Augenklinik, 72076 Tübingen, Baden-Württemberg, Germany; dominik.fischer{at}uni-tuebingen.de

Abstract

Background/aims Voretigene neparvovec (VN) is the first and only subretinal gene therapy approved by the Food and Drug Administration and European Medicines Agency. Real-world application has started in 2018 in patients with vision impairment due to biallelic retinal pigment epithelium (RPE) 65 mutation-associated inherited retinal degenerations. Herein, we evaluated the development of retinal atrophy within in a single-centre patient cohort treated with VN.

Methods 13 eyes of eight patients treated with VN were retrospectively analysed for areas of retinal atrophy over a period of 6–24 months following surgery. Ultrawide field images were used to measure the area of atrophy. Fundus autofluorescence imaging is presented as an instrument for early detection of signs of retinal atrophy in these patients.

Results Atrophic changes beyond the retinotomy site were observed in all eyes. Areas of atrophy developed within the area of detachment (bleb) in all eight patients and outside the bleb in three patients. Changes in autofluorescence preceded the development of retinal atrophy and were already evident 2 weeks after surgery in the majority of patients. The areas of atrophy increase with time and progression continued over year 1. Functional outcomes remained stable (VA, FST, visual field).

Conclusion Subretinal injection of VN can lead to RPE atrophy with consequent photoreceptor loss in and outside of the bleb area. Fundus autofluorescence is an important tool to monitor atrophic changes in patients after gene therapy. Interestingly, while areas of atrophy also included central areas, the functional benefits of the treatment did not appear to be affected and remained stable.

  • Drugs
  • Degeneration
  • Retina
  • Treatment Surgery

Data availability statement

Data are available upon reasonable request. The authors confirm that the most relevant data supporting the findings of this study are available within the article and its supplementary materials. Additional data supporting the findings of this study are available from the corresponding author, [M.D. Fischer], upon reasonable request.

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Data availability statement

Data are available upon reasonable request. The authors confirm that the most relevant data supporting the findings of this study are available within the article and its supplementary materials. Additional data supporting the findings of this study are available from the corresponding author, [M.D. Fischer], upon reasonable request.

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Footnotes

  • Contributors Concept and design: MDF, FFR, KS, KUB-S; acquisition, analysis or interpretation of data: FFR, MDF, IS, KS, KUBS, drafting of the manuscript: FFR, MDF, KS; critical revision of the manuscript for important intellectual content: FFR, MDF, KS, IS, FW, SD, RJ, MK, SK, FCK, SO, LP, KS, KUB-S; statistical analysis: FFR, MDF, IS; administrative, technical or material support: IS, FW, SD, RJ, MK, SK, FCK, SO, LP, KS, KUB-S. Overall guarantor: MDF.

  • Funding Felix Reichel received funding from the German Clinician Scientist program (486-0-0).

  • Competing interests DF is on the advisory board of and/or consulting and/or receiving honoraria/grant money/travel support from following companies: Adelphi Values, Advent France Biotechnology, Alphasights, Arctos Medical, Atheneum, Axiom Healthcare Strategies, Biogen, Cambridge Consultants, Decision Resources, Dialectica, Frontera Therapeutics, Janssen Research & Development, Navigant, Novartis, Roche, RegenxBio, Sirion, System Analytic, and STZeyetrial. He is director of Fischer Consulting Limited and holds a patent (50%) on a gene therapy product for X-linked Retinitis Pigmentosa. FW reports personal fees from Novartis, outside the submitted work. KS reports personal fees from Novartis, outside the submitted work. SK reports grants from Charlotte & Tistou Kerstan Foundation, during the conduct of the study; personal fees from Novartis, outside the submitted work. No other disclosures were reported.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.