Structure-Function Relationships in Stargardt Disease.

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Project Summary/Abstract ABCA4 gene related Stargardt disease (STGD1) is the most common juvenile macular dystrophy and can affect both children and adults. It is inherited as an autosomal-recessive trait associated with mutations in the ABCA4 gene. Patients experience a slow progressive loss of visual function, especially central vision, and can reach legal blindness in decades. Currently there is no approved treatment for STGD1. Potential treatment options include pharmacologic, gene replacement and stem-cell transplantation approaches. Success of future STGD1 treatment trials will depend on appropriately selected trial endpoints. Regulatory agencies prefer visual function outcomes which however can be inefficient for STGD1 trials because of the slow rates of visual function loss in the disease natural history. Retinal structural parameters (SP) measured by fundus autofluorescence (FAF) and optical coherence tomography (OCT) imaging are widely used clinically to track disease progression. However, before accepting an SP as a trial endpoint, regulatory agencies require evidence of significant relationships between the SP and functional outcomes, including both cross-sectional relationships and also longitudinal associations between structural changes and “a future clinically significant outcome”. Such evidence (or lack of) has not been well demonstrated for STGD1. The Progression of Atrophy Secondary to Stargardt Disease (ProgStar) prospective study, including its ancillary Scotopic Microperimetric Assessment of Rod Function in Stargardt Disease (SMART) study, is a multi-center international study of 259 molecularly confirmed STGD1 patients to generate natural history data over 2 years of follow-up. Leveraging data from these studies, our aims are: First, to assess cross-sectional and longitudinal associations of FAF derived parameters on atrophic lesion size with functional outcomes of best corrected visual acuity (BCVA) and macula sensitivities from photopic and scotopic microperimetry tests. Second, to assess cross-sectional and longitudinal associations of OCT derived parameters on retinal integrity, including thicknesses and intact areas of the inner and outer retinal layers, with functional outcomes of BCVA and photopic and scotopic macula sensitivities. Generalized linear models with generalized estimating equation will be used. The knowledge learned will demonstrate what FAF and OCT derived SPs, at what magnitudes, and under what phenotypic conditions, are associated with loss of visual functions, thus leading to a better understanding of the disease pathophysiology. The knowledge will inform choices of endpoints and enrollment criteria for forthcoming STGD1 treatment trials.