Surgical Aspects in Gene Therapy for Inherited Retinal Diseases

Abstract

Inherited retinal dystrophies (IRD) have been studied since their recognition by Franz Donders and Albrecht von Graefe. It nevertheless took 100 years for a causal therapy to take shape in the form of gene therapy: The approval of Voretigen Neparvovec (VN) for the treatment of hereditary retinal dystrophies due to RPE65 mutations was thus a significant milestone – for the era of personalised medicine in general and ophthalmology in particular. The clinical management around gene therapy applications is complex and requires the cooperation of various experts as a multidisciplinary team. This article describes the requirements, challenges, approaches, and open questions regarding the surgical aspects of gene therapy for retinal dystrophies. The first part outlines the standard surgical treatment. Based on this standard, alternative approaches are indicated for each individual step and their value discussed. Knowledge gaps are defined and in the outlook we speculate on future developments.

Key words

retina - dystrophy - gene therapy

• References/Literatur

• 1 Donders FC. Beiträge zur pathologischen Anatomie des Auges; 2) Pigmentbildung in der Netzhaut. Graefes Arch Clin Exp Ophthalmol 1857; 3: 139-150
• 2 von Graefe A. Vereinzelte Beobachtungen und Bemerkungen. Exceptionelles Verhalten des Gesichtsfeldes bei Pigmententartung der Netzhaut. Arch Ophthalmol 1858; 4: 250-253
• 3 Russell S, Bennett J, Wellman JA. et al. 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 2017; 390: 849-860 doi:10.1016/S0140-6736(17)31868-8
• 4 Deutsche Ophthalmologische Gesellschaft (DOG), Retinologische Gesellschaft e. V. (RG), Berufsverband der Augenärzte Deutschlands e. V. (BVA). Stellungnahme von DOG, RG und BVA zur therapeutischen Anwendung von voretigene neparvovec (Luxturna^™) in der Augenheilkunde. Klin Monbl Augenheilkd 2019; 236: 816-824 doi:10.1055/a-0899-6601
• 5 Bainbridge JW, Smith AJ, Barker SS. et al. Effect of gene therapy on visual function in Leberʼs congenital amaurosis. N Engl J Med 2008; 358: 2231-2239 doi:10.1056/NEJMoa0802268
• 6 Gan NY, Lam WC. Special considerations for pediatric vitreoretinal surgery. Taiwan J Ophthalmol 2018; 8: 237-242 doi:10.4103/tjo.tjo_83_18
• 7 Kita M, Negi A, Kawano S. et al. Measurement of retinal adhesive force in the in vivo rabbit eye. Invest Ophthalmol Vis Sci 1990; 31: 624-628
• 8 Fischer MD, Hickey DG, Singh MS. et al. Evaluation of an Optimized Injection System for Retinal Gene Therapy in Human Patients. Hum Gene Ther Methods 2016; 27: 150-158 doi:10.1089/hgtb.2016.086
• 9 Maguire AM, Simonelli F, Pierce EA. et al. Safety and efficacy of gene transfer for Leberʼs congenital amaurosis. N Engl J Med 2008; 358: 2240-2248 doi:10.1056/NEJMoa0802315
• 10 Fischer MD, Michalakis S, Wilhelm B. et al. Safety and Vision Outcomes of Subretinal Gene Therapy Targeting Cone Photoreceptors in Achromatopsia: A Nonrandomized Controlled Trial. JAMA Ophthalmol 2020; 138: 643-651 doi:10.1001/jamaophthalmol.2020.1032
• 11 Fischer MD, Ochakovski GA, Beier B. et al. Changes in Retinal Sensitivity after Gene Therapy in Choroideremia. Retina 2020; 40: 160-168 doi:10.1097/IAE.0000000000002360
• 12 Seitz IP, Fischer MD. [The Natural History of Choroideraemia]. Klin Monbl Augenheilkd 2019; 236: 236-243 doi:10.1055/a-0841-3417
• 13 Seitz IP, Zhour A, Kohl S. et al. Multimodal assessment of choroideremia patients defines pre-treatment characteristics. Graefes Arch Clin Exp Ophthalmol 2015; 253: 2143-2150 doi:10.1007/s00417-015-2976-4
• 14 MacLaren RE, Groppe M, Barnard AR. et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet 2014; 383: 1129-1137 doi:10.1016/S0140-6736(13)62117-0
• 15 Xue K, Groppe M, Salvetti AP. et al. Technique of retinal gene therapy: delivery of viral vector into the subretinal space. Eye (Lond) 2017; 31: 1308-1316 doi:10.1038/eye.2017.158
• 16 Fischer MD, Ochakovski GA, Beier B. et al. Changes in retinal sensitivity after gene therapy in choroideremia. Retina 2020; 40: 160-168 doi:10.1097/iae.0000000000002360
• 17 Davis JL, Gregori NZ, MacLaren RE. et al. Surgical Technique for Subretinal Gene Therapy in Humans with Inherited Retinal Degeneration. Retina 2019; 39 (Suppl. 01) S2-S8 doi:10.1097/IAE.0000000000002609
• 18 Heimann H, Bopp S. Retinal folds following retinal detachment surgery. Ophthalmologica 2011; 226 (Suppl. 01) S18-S26 doi:10.1159/000328380
• 19 Bucher K, Rodríguez-Bocanegra E, Dauletbekov D. et al. Immune responses to retinal gene therapy using adeno-associated viral vectors – Implications for treatment success and safety. Prog Retin Eye Res 2020;