Risk factors for disease progression in eyes with geographic atrophy (GA)
Final Report Abstract
Primary objective of this project was to analyze the progression of GA by high-resolution retinal imaging. GA is the atrophic late stage (‘dry’) of age-related macular degeneration (AMD). While the ‘wet‘ form of AMD, that is characterized by the development of chorodial neovascularzation (CNV), can be treated by repetitive anti vascular endothelial growth factor therapy, there is yet no effective treatment available to halt or slow down GA progression. The progression of GA is associated with a decrease in visual function that include expanding visual field defects, a decline in central vision and reading difficulties. Hence, GA represents a condition that highly effects the quality of life of affected patients. To develop effective therapies for GA, knowledge of the natural disease course is pivotal. In the context of the funded research project, we were able to describe distinct expansion patterns of GA and to identify new prognostic markers for disease progression that include specific GA border characteristics visualized by high-resolution optical coherence tomography imaging. We further analyzed the factors that explain up to 39% of the variability of GA progression between eyes/patient. These findings are of importance both for a patient’s individual outcome as well as for the design of future interventional clinical trials. Knowledge of relevant prognostic factors facilitates to identify patients at high risk for fast disease progression. Accordingly, the design for interventional trials could be adapted in order to reduce the observation period, sample size, and costs. Of note, our results have already been considered in the design of interventional trials in GA and are currently basis for the conception of a gene-based therapy trial in AMD that is planned to be conducted at the Sharon Eccles Steele Center for Translational Medicine (SCTM), Moran Eye Center, University of Utah, Salt Lake City, USA. A major challenge in interventional trials to slow down or halt GA, is to show a potential treatment effect. There is indeed concern at present that the effectiveness of innovative therapeutic approaches cannot be proven by the currently established primary outcome measures (i.e. central visual acuity and GA progression). With the desing of ‘lesion-tailored fundus-controlled perimetry (FCP) grids’, that allow for testing of retinal function in the border-zone of GA, we were able to develop a strategy to test retinal sensitivity at the critical locations in the disease process. Notably, the FDA (U.S. Food and Drug Administration) is considering to accept FCP as primary outcome measure in AMD trials. Accordingly, we are currently conducting a prospective natural history study in AMD patients at the SCTM to further validate FCP as outcome measure for a clinically meaningful endpoint. In regard to the correlation of structural changes with functional deficit in eyes with GA, we found that the decline in vision and reading performance is dependent on distinct GA lesion characteristics. Exemplarily, in a subset of patients with ‘foveal sparing’ GA, i.e. when the area of sharpest vision is spared by the atrophic process, we assessed the area on the retina that is required for unhindered reading. Interestingly, we saw that smaller test sentences could be read faster by patients with this AMD sub-phenotype. These findings allow prediction of reading impairment based on imaging parameters in clinical routine and can be used to facilitate the adjustment of magnifying reading aids. The most astonishing observation in the context of the funded research project was that CNV membranes that co-localize with GA may reduced the progression of the diseases. This finding together with observations from other research groups indeed represents a paradigm shift in understanding AMD progression. It underscores a potential protective mechanism of CNV evolution in AMD. These results have relevant clinical implications for the management of ‘wet‘ AMD and may lead to new therapeutic strategies to prevent atrophy progression. Hence, a major focus of our current research is to further analyze the impact of CNV on atrophic AMD progression. The unique environment of the SCTM will allow consolidating genetic as well as histopathological data to further substantiate the hypotheses generated by in vivo high-resolution retinal imaging.
Publications
- Choroidal thickness in geographic atrophy secondary to age-related macular degeneration. Invest Ophthalmol Vis Sci. 2015;56:875-82
Lindner M, Bezatis A, Czauderna J, Becker E, Brinkmann CK, Schmitz-Valckenberg S, Fimmers R, Holz FG, Fleckenstein M
(See online at https://doi.org/10.1167/iovs.14-14933) - Directional Kinetics of Geographic Atrophy Progression in Age-Related Macular Degeneration with Foveal Sparing. Ophthalmology. 2015;122:1356-65
Lindner M, Böker A, Mauschitz MM, Göbel AP, Fimmers R, Brinkmann CK, Schmitz-Valckenberg S, Schmid M, Holz FG, Fleckenstein M, Fundus Autofluorescence in Age-Related Macular Degeneration Study Group
(See online at https://doi.org/10.1016/j.ophtha.2015.03.027) - Modeling Visual Acuity in Geographic Atrophy Secondary to Age-Related Macular Degeneration. Ophthalmologica. 2016;235:215-24
Schmitz-Valckenberg S, Nadal J, Fimmers R, Lindner M, Holz FG, Schmid M, Fleckenstein M. FAM Study Group
(See online at https://doi.org/10.1159/000445217) - OCT Angiography–Based Detection and Quantification of the Neovascular Network in Exudative AMD. Invest Ophthalmol Vis Sci. 2016;57:6342-6348
Lindner M, Fang PP, Steinberg JS, Domdei N, Pfau M, Krohne TU, Schmitz-Valckenberg S, Holz FG, Fleckenstein M
(See online at https://doi.org/10.1167/iovs.16-19741) - Combined Fundus Autofluorescence and Near Infrared Reflectance as Prognostic Biomarkers for Visual Acuity in Foveal-Sparing Geographic Atrophy. Invest Ophthalmol Vis Sci. 2017;58:BIO61-BIO67
Lindner M, Nadal J, Mauschitz MM, Lüning A, Czauderna J, Pfau M, Schmitz-Valckenberg S, Holz FG, Schmid M, Fleckenstein M
(See online at https://doi.org/10.1167/iovs.16-21210) - Differential Disease Progression in Atrophic Age-Related Macular Degeneration and Late-Onset Stargardt Disease. Invest Ophthalmol Vis Sci. 2017;58:1001-1007
Lindner M, Lambertus S, Mauschitz MM, Bax NM, Kersten E, Lüning A, Nadal J, Schmitz- Valckenberg S, Schmid M, Holz FG, Hoyng CB, Fleckenstein M; Foveal sparing Atrophy Study Team (FAST)
(See online at https://doi.org/10.1167/iovs.16-20980) - Local Progression Kinetics of Geographic Atrophy in Age- Related Macular Degeneration Are Associated With Atrophy Border Morphology. Invest Ophthalmol Vis Sci. 2018;59:AMD12-AMD18
Lindner M, Kosanetzky S, Pfau M, Nadal J, Gördt LA, Schmitz-Valckenberg S, Schmid M, Holz FG, Fleckenstein M; FAM-Study Group
(See online at https://doi.org/10.1167/iovs.17-23203) - The Progression of Geographic Atrophy Secondary to Age-Related Macular Degeneration. Ophthalmology. 2018;125:369-390
Fleckenstein M, Mitchell P, Freund KB, Sadda S, Holz FG, Brittain C, Henry EC, Ferrara D
(See online at https://doi.org/10.1016/j.ophtha.2017.08.038) - Determinants of Reading Performance in Eyes with Foveal-Sparing Geographic Atrophy. Ophthalmol Retina. 2019;3:201-210
Lindner M, Pfau M, Czauderna J, Goerdt L, Schmitz-Valckenberg S, Holz FG, Fleckenstein M
(See online at https://doi.org/10.1016/j.oret.2018.11.005) - Prognostic value of shape-descriptive factors for the progression of geographic atrophy secondary to age-related macular degeneration. Retina. 2019;39:1527-1540
Pfau M, Lindner M, Goerdt L, Thiele S, Nadal J, Schmid M, Schmitz-Valckenberg S, Sadda SR, Holz FG, Fleckenstein M; Fundus Autofluorescence in Age-Related Macular Degeneration Study group
(See online at https://doi.org/10.1097/IAE.0000000000002206) - Mesopic and Dark-adapted Two-color Fundus-controlled Perimetry in Geographic Atrophy secondary to Age-related Macular Degeneration. Retina. 2020;40:169-180
Pfau M, Müller PL, von der Emde L, Lindner M, Möller PT, Fleckenstein M, Holz FG, Schmitz- Valckenberg S
(See online at https://doi.org/10.1097/IAE.0000000000002337) - Type 1 Choroidal Neovascularization Is Associated with Reduced Localized Progression of Atrophy in Age-Related Macular Degeneration. Ophthalmol Retina. 2020;4:238-248
Pfau M, Möller PT, Künzel SH, von der Emde L, Lindner M, Thiele S, Dysli C, Nadal J, Schmid M, Schmitz-Valckenberg S, Holz FG, Fleckenstein M
(See online at https://doi.org/10.1016/j.oret.2019.09.016)
