Natural Course of Atrophy Growth Rate on Fundus Autofluorescence in a Large Cohort of Stargardt Patients

Abstract

Purpose : Stargardt disease (STGD1) is a rare and highly heterogenous disease predominantly characterized by progressive central macular atrophy. Currently, there is no treatment for STGD1. New therapeutic options are emerging, including antisense oligonucleotide (AON)-based splicing modulation therapy. Designing trials for both rare and heterogeneous diseases is challenging. The right endpoint must be selected to reach sufficient statistical power while minimizing sample size and study duration. Retinal atrophy growth is an accepted endpoint already being used in age-dependent macular degeneration. The current study aims to elucidate the precise growth in atrophy area in STGD1 as observed through fundus autofluorescence (FAF).

Methods : We included all genetically confirmed STGD1 patients from the Radboudumc STGD1 database with at least two FAF images (201 patients, 399 eyes). Subgroups were made based on age of onset (early-onset ≤10 years, intermediate-onset 11-44 years, late-onset ≥45 years) and based on ABCA4 mutations eligible for future AON-based therapy (c.768G>T or c.4539+2001G>A). Genetically confirmed STGD1 patients from Ghent University Hospital carrying one of these two mutations were added to the mutation specific analysis to increase sample size (19 patients, 37 eyes).
Area of definitely and total decreased autofluorescence (DDAF and TDAF) were measured using the Heidelberg Regionfinder software (Heidelberg, Germany). Square root transformation was used to correct for two-dimensional growth. A mixed model was used to determine the atrophy growth rates.

Results : DDAF growth rate was 0.1473 mm/year (95% CI 0.1405 – 0.1540 mm/year). TDAF growth rate was 0.1486 mm/year (95% CI 0.1427 – 0.1546 mm/year).
TDAF was significantly different between all age of onset groups. Early onset had the highest growth rate: 0.1898 mm/year (95% CI 0.1750 – 0.2048), followed by late onset: 0.1707 mm/year (95% CI 0.1592 – 0.1822) and intermediate onset 0.1295 mm/year (95% CI 0.1219 – 0.1370).
Patients carrying the c.768G>T variant had significantly faster TDAF growth compared to patients with c.4539+2001G>A (p=0.012), and patients with other ABCA4 mutations (p=0.014).

Conclusions : Atrophy growth rates vary among subgroups of STGD1 patients, depending on both age of onset and specific mutations. This underlines the importance of categorizing STGD1 patients into homogeneous groups to improve trial efficiency.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.