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Retinal gene supplementation therapy such as the first approved one, voretigene neparvovec, delivers a functioning copy of the missing gene enabling the protein transcription in retinal cells and restore visual functions. After gene supplementation for the genetic defect, a complex network of functional regeneration is the consequence, whereas the extent is very individualized. Diagnostic and functional testings that have been used routinely by ophthalmologists so far to define the correct diagnosis, cannot be applied in the new context of defining small, sometimes subtle changes in visual functions. New view on retinal diagnostics is needed to understand this processes that define safety and efficacy of the treatment. Not only does vision have many aspects that must be addressed by specific evaluations and imaging techniques, but objective readouts of local retinal function for rods and cones separately have been an unmet need until recently. A reliable test-retest variability is necessary in rare diseases such as inherited retinal dystrophies, because statistics are often not applicable due to a low number of participants. Methods for a reliable individual evaluation of the therapy success are needed. In this manuscript we present an elaboration on retinal diagnostics combining psychophysics (eg. full-field stimulus threshold or dark adapted perimetry) as well as objective measures for local retinal function (eg. photopic and scotopic chromatic pupil campimetry) and retinal imaging for a meaningful workflow to apply in evaluation of the individual success in patients receiving gene therapy for photoreceptor diseases.

Purpose Leber congenital amaurosis type 2 (LCA2) and early-onset severe retinal dystrophy (EOSRD) are linked to visual impairment with nyctalopia and visual acuity reduction in early childhood. In 2017, the first gene therapy voretigene neparvovec (Luxturna™) for patients with LCA and EOSRD cause by bi-allelic mutations in the RPE65 gene has been approved. Here we report on an example of short-term change in the foveal morphology after functionally successful gene therapy with voretigene neparvovec in a 15-year old patient. Methods The clinical examinations included best corrected visual acuity (BCVA), spectral domain optical coherence tomography (OCT) and adaptive optics retinal imaging. Results During follow-up over a period of 3 months after the treatment, an improvement of the central foveal morphology could be observed in OCT, with a clear demarcation of the external limiting membrane and changes in the photoreceptor mosaic on adaptive optics retinal imaging. These morphological rescue parameters correlated in part with the improvement in foveal-mediated vision after the treatment and adaptive optics imaging. Although the visual acuity improved only slightly at month 3, objective central cone evaluation with chromatic pupil campimetry showed an increase in the central sensitivity. In daily life, the patient reported her visional experience after the treatment as 'brighter'. Conclusion Rapid changes in the correlates of photoreceptor morphology after successful gene therapy in patients with LCA/EORD can be quantifiable on individual level.

Background/aimsVoretigene 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.Methods13 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.ResultsAtrophic 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).ConclusionSubretinal 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.