Abstract
Purpose :
Retinitis pigmentosa (RP) comprises a group of progressive inherited retinal dystrophies characterized by sequential loss of rod then cone photoreceptors, resulting in disabling vision impairment. Our investigational treatment, IGT001, aims to rescue diseased photoreceptors by utilizing encapsulated human rod precursor cells that act by secreting protective protein factors. We demonstrate robust anatomical and functional efficacy across three mutant mouse models of RP. Additionally, unbiased proteomic analysis identified a subset of key secreted proteins underlying these phenotypic improvements in models
Methods :
Rho, rd10, and P23H mutant mouse lines were used and IGT001 was intravitreally injected at disease stage analogous to mid-stage RP. IGT001 comprises hRPs encapsulated within a biomimetic hydrogel scaffold for intravitreal injection using a translational delivery platform. Testing included histological, electrophysiological, and behavioural assessments longitudinally. In parallel experiments, conditioned media harvested from hRP cultures underwent quantitative mass spectrometry-based profiling followed by sequential in vitro and in silico screening steps to delineate key factors and mechanisms conferring neuroprotective and repair properties.
Results :
Across models, IGT001 elicited >40% increased cone photoreceptor survival versus sham controls based on central retinal histology. Rescued cells maintained outer segment integrity, suggesting preserved function. This anatomical preservation was accompanied by significant gains in electrical responses to light stimuli, with x2 fold greater photopic b-wave amplitudes and cognitive optomotor reflexes, together indicating recovery of visual capacity compared to rapid deterioration in control. Proteomics identified over 300 secreted proteins, of which subsequent target validation studies functionally confirmed 10 factors modulating pathogenic processes from glycolysis dysfunction to protein misfolding as central drivers of the multifaceted treatment effects observed.
Conclusions :
In three distinct genetic RP models, sustained delivery of trophic factors by intravitreally injected allogeneic hRPCs safely preserved cone photoreceptors and visual function. Elucidating responsible protein agents and mechanisms enables optimizing potency. This platform technology may enable mutation-agnostic intervention amidst disease heterogeneity by restoring cone functions.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.