Spatial and temporal resolution of the photoreceptors rescue dynamics after treatment with voretigene neparvovec

Abstract

BackgroundVoretigene neparvovec is a gene therapeutic agent for treatment of retinal dystrophies caused by bi-allelic RPE65 mutations. In this study, we report on a novel and objective evaluation of a retinotopic photoreceptor rescue.MethodsSeven eyes of five patients (14, 21, 23, 24, 36 years, 1 male, 4 females) with bi-allelic RPE65 mutations have been treated with voretigene neparvovec. The clinical examinations included visual acuity testing, dark-adapted full-field stimulus threshold (FST), dark-adapted chromatic perimeter (DAC) with a 30-degree grid, and a 30 degrees grid scotopic and photopic chromatic pupil campimetry (CPC). All evaluations and spectral domain optical coherence tomography were performed at baseline, 1 month and 3 months.ResultsAll except the oldest patient had a measurable improvement of the rod function assessed via FST, DAC or scotopic CPC at 1 month. The visual acuity improved slightly or remained stable in all eyes. A cone function improvement as measured by photopic CPC was observed in three eyes. The gain of the dark-adapted threshold with blue FST and the DAC stimuli (cyan) average correlated strongly with age (R2>0.7). The pupil response improvement in the scotopic CPC correlated with the baseline local retinal volume (R2=0.5).ConclusionsThe presented protocols allow evaluating the individual spatial and temporal effects of gene therapy effects. Additionally, we explored parameters that correlated with the success of the therapy. CPC and DAC present new and fast ways to assess functional changes in retinotopic maps of rod and cone function, measuring complementary aspects of retinal function.

CRB1-Associated Retinal Dystrophies: A Prospective Natural History Study in Anticipation of Future Clinical Trials

“…Novel outcome measurements used in the assessment of gene therapy, such as multi-luminance mobility tests, darkadapted chromatic perimetry and pupil campimetry, were also not assessed in this study. 58,59 Future studies that follow a large group of patients with CRB1 variants over a longer period of time, while also assessing the feasibility of more recent outcome measures, would be invaluable to extend our current findings.…”

Short term morphological rescue of the fovea after gene therapy with voretigene neparvovec

“…In Europe, the medication was approved for treatment in November 2018. Clinical trials before and after approval show that the degeneration process can be slowed down by this gene supplementation therapy in treated patients, but also a functional improvement especially in young patients is possible (Jacobson et al, 2012;Testa et al, 2013;Stingl et al, 2021).…”

How lesions at different locations along the visual pathway influence pupillary reactions to chromatic stimuli

“…However, spatial pupillographic strategies, such as chromatic pupil campimetry (CPC) [5,6], are of increasing importance, as they objectively provide information of local functionality for natural history observations as well as follow-up after therapeutic intervention in patients with specific retinal diseases. Defects on retinal level, e.g., rod-cone dystrophies or age-related macular degeneration, are precisely detectable by CPC [6][7][8][9].…”