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Fundus autofluorescence assessment tracks Stargardt disease progression for a 24-month period. 

Researchers at the Department of Ophthalmology, Medical University Graz, Austria and the Department of Ophthalmology, University of Basel, Switzerland, have reported that fundus auto-fluorescence (FAF) data may provide valuable monitoring tools and clinical endpoints for interventional clinical trials with Stargardt disease patients (STGD1).  According to a published paper in the journal of American Journal of Ophthalmology (Feb. 8th, 2023), data has shown that the annual rate of progression of STGD1, reflected by the growth of atrophic lesions measured by FAF imaging after 24 months of observation, has “been accepted as a surrogate endpoint by regulatory authorities”.  The researchers commented that, “FAF imaging provides potential endpoints to track disease progression in STGD1 patients, especially the growth rate of DDAF (definitely decreased auto-fluorescence) lesions. These data should provide useful information for the design of clinical trials to treat STGD1”.

Stargardt disease (STGD1) is caused by mutations in the photoreceptor-specific ABCA4 gene which encodes the adenosine triphosphate-binding cassette, subfamily A, member 4.  The ABCA4 gene encodes a transporter protein within retinal photoreceptor cells facilitating the active transport of potentially toxic retinoid compounds removing toxic by-products from the visual cycle.  A number of pathogenic variants within certain introns of the ABCA4 gene may result aberrant splicing of the gene – including pseudogenes – essentially non-functional segments of DNA.  Splicing defects within pseudogenes of ABCA4 can insert aberrant “pseudoexons” (PEs) into the ABCA4 pre-mRNA.   The recent research study was a prospective multicentre observational cohort trial, labelled “ProgStar”, conducted at six centres in the U.S.A, and one each in France, Germany and the United Kingdom. Two-hundred and fifty-nine (259) participants were recruited, aged from  ≥6 years with disease-causing variants in the ABCA4 gene, were enrolled from nine centres and followed over a 24 month period. The FAF images were obtained every 6 months and areas of definitely decreased autofluorescence (DDAF) and decreased autofluorescence (DAF) were quantified using the Doheny Imaging Reading Center (DIRC). The outcome variables (total DAF area, DDAF area, and effective lesion radius of total DAF and DDAF) were calculated as square root transformation, SQRT=√(lesion area/π)) using a linear mixed model (LMM), with time as the independent variable, and was used to estimate the yearly growth of each outcome.

The results of the study reported that 488 study eyes of 259 participants (88.8% with both eyes) were enrolled and images from 432 eyes were followed for 24-months. The overall estimated progression of DDAF was recorded 0.74 (confidence interval (CI) 0.64 – 0.85; p<.0001) mm2/year, and of DAF was 0.64 (CI 0.57 – 0.71) mm2/year over the 24 month period in univariate analysis. The researchers stated that the growth rates were strongly dependent on the baseline lesion area and after square root transformation, DDAF growth rate was not dependent on baseline lesion radius (p=0.11), while DAF growth rate was dependent (p<.0001). In addition, the assessment of the genotype data was not found to significantly impact growth rate of DDAF or DAF lesions.  Finally, their report commented that while former smokers had faster lesion growth in univariate analysis, the associations were not statistically significant in multivariate analysis. However, the researchers stated, “smoking has numerous negative ocular health effects, including with respect to retinal diseases, such as AMD, and in monogenic diseases like retinitis pigmentosa, where an association of smoking with worse structural integrity in has been described”.