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Tackling Age-related Macular Degeneration from different angles

Professor Frank G. Holz

The research work of Professor Dr. Frank G. Holz

Age-related macular degeneration (AMD) is a leading cause for global blindness. Despite a major therapeutic breakthrough in neovascular disease states, the advanced atrophic late-stage manifestation (geographic atrophy - GA), with exponential increase in prevalence with age, represents a major unmet need. Earlier stages of the disease including intermediate AMD not only lack a treatment for halting or slowing progression, but also an approvable endpoint for testing efficacy of potential interventions. A multidisciplinary approach with both basic and clinical science is needed to better understand the underlying pathophysiology, to identify treatment targets and ultimately to develop efficacious therapies. This was the starting point when we early on established a DFG (German Research Council) priority research program (SPP 1088) “age-related macular degeneration” encompassing multifaceted disciplines. A base was formed for many subsequent collaborations both nationally and internationally as well as for later research funding.

Novel disease biomarkers and outcome measures

Fundus autofluorescence (FAF) imaging using confocal scanning laser ophthalmoscopy (cSLO) allows for topographic mapping of naturally or pathologically occurring intrinsic fluorophores. The dominant sources are fluorophores accumulating in the lysosomal compartment of postmitotic retinal pigment epithelium cells as well as other fluorophores that may occur with disease in the outer retina and subretinal space. FAF imaging has been shown to be useful with regard to understanding of pathophysiological mechanisms, diagnostics, phenotype-genotype correlation, identification of prognostic markers for disease progression, and novel outcome parameters to assess efficacy of interventional strategies in retinal diseases. More recently, the spectrum of FAF imaging has been expanded with use of green FAF, introduction of spectrally-resolved FAF, near-infrared FAF, and quantitative FAF imaging.

We have shown that FAF imaging is one of the most reliable imaging modalities to detect, delineate, reproducibly quantify, and monitor progression of outer retinal atrophy. The loss of RPE and its inherent fluorophores in GA correlates with well-defined areas of decreased autofluorescence, allowing for precise manual, semi-automatic or automatic GA segmentation methods based on FAF imaging. Hereby, the semi-automatic region-growing image analysis approach has been integrated in a now commercially available software (RegionFinderTM  Heidelberg Engineering).

Based on various natural history studies including the FAM-study conducted by our team GA lesion growth based on FAF imaging has become an accepted primary structural outcome measure by the regulatory authorities including FDA in prospective interventional GA-trials.

A striking finding of FAF imaging in GA is the frequent presence of areas of relative increased FAF in the junctional zone surrounding atrophic patches. Looking at larger patient groups with longer review periods, the significance of increased junctional FAF for foreshadowing atrophy enlargement has been demonstrated Distinct patterns of abnormal FAF in the junctional zone of atrophy and a high degree of intraindividual symmetry between fellow eyes have subsequently been described by our group. A classification system of abnormal FAF patterns in the junctional zone of atrophy in GA patients has been developed, used as inclusion criterion for patient selection in GA-trials (fast progressors). Furthermore, studies of retinal sensitivity have underscored the relevance of FAF surrounding areas of GA

In addition to FAF patterns in the junctional zone we showed that several other factors can inform an individual’s disease prognosis including baseline lesion size, lesion location, multifocality, presence of reticular pseudodrusen and fellow eye status. Correlations with other imaging modalities has subsequently been sought by the international CAM-group (Classification of Atrophy Meeting) who also addressed the sequence from incomplete to complete outer retinal atrophy in the context of AMD.

FAF imaging is now widely used also in the context of other complex and monogenetic retinal degenerations. As an example in a rare disease our group found a abnormally increased FAF signal in the macular area to a variable degree with blue-light FAF imaging in eyes with macular telangiectasia (MacTel) type 2 due to deficiencies in trafficking and storage of luteal pigment. This is now considered a hallmark phenotypic feature in this slowly progressive neurodegenerative disease of the central retina and also serves as a prognostic biomarker.

Example for atrophy quantification over time. First row: near-infrared reflectance images at baseline, month 6, and month 12; second row: native fundus autofluorescence images; third row: results of reader 1; the detected areas of atrophic are highlighted in blu; fourth row: results of reader 2. (Schmitz-Valckenberg et al. 2011)
Lesion features associated with progression of geographic atrophy (GA). Lesion features on (A) fundus autofluorescence (FAF) and (B) OCT. Dotted line: extent of convex hull; black arrow: vitreoretinal traction; black arrowhead: outer retinal tubulation; white arrowheads: reticular pseudodrusen; asterisks: soft drusen; vertical bar: choroidal thickness. (Fleckenstein et al. 2018)

Genetic factors – novel therapeutic targets

To probe potential genetic factors various studies have been conducted with Bernhard Weber’s group (University of Regensburg). Recently, in 935 patients with longitudinal GA progression data were analyzed to determine the contribution of common genetic variants to GA lesion growth. Two gene loci with conservative genome-wide significance were identified. Each minor allele of the genome-wide associated variants increased the GA growth rate by a mean of about 15% or 0.05 mm per year. Gene prioritization within each locus suggested the protein arginine methyltransferase 6 gene (PRMT6) and the lanosterol synthase gene (LSS) as the most likely progression-associated genes.

Artificial intelligence for retinal image and structure-function analysis

Artificial intelligence (AI)/deep learning offers a new horizon for analyzing digital images and personalized medicine based on these analyses. Human visual grading of retinal images is inherently limited, e.g. by the required time/ressources and limited visual resolution of humans. We are particularly interested in automated quantifications of AMD features on OCT such as different phenotypes of drusen, focal high-risk pigmentary changes quantification as well as in mapping retinal function de novo in order to provide an en-face high-resolution map of predicted retinal sensitivity (“inferred sensitivity”) based on structural information. Hereby machine learning algorithms are applied to predict functional impairment based on multimodal imaging. This may be applicable in future interventional trials to allow for refined investigation of treatment effect superior to standard functional testing without the need for psychophysical examinations such as mesopic and scotopic microperimetry. AI-based quantifications recently also allowed the demonstration of the protective effect of type 1 CNV on the RPE and overlying neurosensory retina in eyes with geographic atrophy with clinical implications for the management of CNV and new therapeutic strategies to prevent atrophy progression.

Segmentation of SD-OCT data and registration of functional fundus-controlled perimetry and imaging data (Pfau et al. 2020)
Feature importance plots. The feature importance plots show the permutation-based importance in terms of the percentage increase in mean squared error (% Inc MSE). The colors indicate the respective retinal structure represented by the respective imaging feature (Pfau et al. 2020).

Intermediate AMD – the holy grail

Preventing late-stage disease by therapeutic intervention may be considered the holy grail in AMD. However, currently, no outcome measures are clinically validated and accepted as clinical endpoints by regulatory agencies for drug development in intermediate age-related macular degeneration. The MACUSTAR consortium, a public-private research group funded by the European Innovative Medicines Initiative, intends to close this gap. A large natural history study across 20 clinical sites in Europe currently ongoing will address structural and functional and patient outcome aspects of intermediate AMD including machine-learning approaches for identifying prognostic biomarkers. This observational study consists of a cross-sectional and a longitudinal part. Functional outcome measures assessed under low contrast and low luminance have the potential to detect progression of visual deficit within iAMD and to late AMD. Structural outcome measures will be multimodal and investigate topographical relationships with function. As clinical endpoints currently accepted by regulators cannot detect functional loss or patient-relevant impact in iAMD, we will clinically validate novel candidate endpoints for iAMD.

Overall structure of the ongoing IMI2-funded EU MACUSTAR study

Key publications

  1. Holz FG, Strauss EC, Schmitz-Valckenberg S, van Lookeren Campagne M. Geographic atrophy: clinical features and potential therapeutic approaches. Ophthalmology. 2014 May;121(5):1079-91
  2. Fleckenstein M, Mitchell P, Freund KB, Sadda S, Holz FG, Brittain C, Henry EC, Ferrara D. The Progression of Geographic Atrophy Secondary to Age-Related Macular Degeneration. Ophthalmology. 2018 Mar;125(3):369-390
  3. Holz FG, Sadda SR, Staurenghi G, Lindner M, Bird AC, Blodi BA, Bottoni F, Chakravarthy U, Chew EY, Csaky K, Curcio CA, Danis R, Fleckenstein M, Freund KB, Grunwald J, Guymer R, Hoyng CB, Jaffe GJ, Liakopoulos S, Monés JM, Oishi A, Pauleikhoff D, Rosenfeld PJ, Sarraf D, Spaide RF, Tadayoni R, Tufail A, Wolf S, Schmitz-Valckenberg S; CAM group. Imaging protocols in clinical studies in advanced age-related macular degeneration: recommendations from Classification of Atrophy Consensus Meetings. Ophthalmology. 2017 Apr;124(4):464-478
  4. Grassmann F, Harsch S, Brandl C, Kiel C, Nürnberg P, Toliat MR, Fleckenstein M, Pfau M, Schmitz-Valckenberg S, Holz FG, Chew EY, Swaroop A, Ratnapriya R, Klein ML, Mulyukov Z, Zamiri P, Weber BHF. Assessment of Novel Genome-Wide Significant Gene Loci and Lesion Growth in Geographic Atrophy Secondary to Age-Related Macular Degeneration. JAMA Ophthalmol. 2019 May 23. doi: 10.1001/jamaophthalmol.2019.1318. [Epub ahead of print]
  5. 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. Prognostic value of shape-descriptive factors for the progression of geographic atrophy secondary to age-related macular degeneration. Retina. 2019 Aug;39(8):1527-1540]
  6. Schmitz-Valckenberg S, Sahel JA, Danis R, Fleckenstein M, Jaffe GJ, Wolf S, Pruente C, Holz FG. Natural history of geographic atrophy progression secondary to age-related macular degeneration (Geographic Atrophy Progression Study). Ophthalmology. 2016 Feb;123(2):361-8
  7. Oishi A, Thiele S, Nadal J, Oishi M, Fleckenstein M, Schmid M, Holz FG, Schmitz-Valckenberg S. Prevalence, Natural Course, and Prognostic Role of Refractile Drusen in Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci. 2017;58:2198-2206.
  8. Thiele S, Nadal J, Pfau M, Saßmannshausen M, Fleckenstein M, Holz FG, Schmid M, Schmitz-Valckenberg S. Prognostic value of intermediate age-related macular degeneration phenotypes for geographic atrophy progression. Br J Ophthalmol. 2020 Apr 8:bjophthalmol-2020-316004. [Online ahead of print]
  9. Finger RP, Schmitz-Valckenberg S, Schmid M, Rubin GS, Dunbar H, Tufail A, Crabb DP, Binns A, Sánchez CI, Margaron P, Normand G, Durbin MK, Luhmann UFO, Zamiri P, Cunha-Vaz J, Asmus F, Holz FG; on behalf of the MACUSTAR consortium. MACUSTAR: Development and Clinical Validation of Functional, Structural, and Patient-Reported Endpoints in Intermediate Age-Related Macular Degeneration. Ophthalmologica. 2019;241:61-72
  10. Pfau M, von der Emde L, Dysli C, Möller PT, Thiele S, Lindner M, Schmid M, Rubin DL, Fleckenstein M, Holz FG, Schmitz-Valckenberg S. Determinants of cone- and rod-function in geographic atrophy: AI-based structure-function correlation. Am J Ophthalmol. 2020 Apr 11:S0002-9394(20)30170-7. doi: 10.1016/j.ajo.2020.04.003. Online ahead of print
  11. Pfau M, Möller PT, Künzel SH, Emde LV, Lindner M, Thiele S, Dysli C, Nadal J, Schmid M, Schmitz-Valckenberg S, Holz FG, Fleckenstein M. Type 1 Choroidal Neovascularization Is Associated with Reduced Localized Progression of Atrophy in Age-Related Macular Degeneration. Ophthalmol Retina. 2020 Mar;4(3):238-248
  12. von der Emde L, Pfau M, Dysli C, Thiele S, Möller PT, Lindner M, Schmid M, Fleckenstein M, Holz FG, Schmitz-Valckenberg S. Artificial intelligence for morphology-based function prediction in neovascular age-related macular degeneration. Sci Rep. 2019 Jul 31;9(1):11132
  13. Grassmann F, Harsch S, Brandl C, Kiel C, Nürnberg P, Toliat MR, Fleckenstein M, Pfau M, Schmitz-Valckenberg S, Holz FG, Chew EY, Swaroop A, Ratnapriya R, Klein ML, Mulyukov Z, Zamiri P, Weber BHF. Assessment of Novel Genome-Wide Significant Gene Loci and Lesion Growth in Geographic Atrophy Secondary to Age-Related Macular Degeneration. JAMA Ophthalmol. 2019 May 23:e191318. doi: 10.1001/jamaophthalmol.2019.1318. Online ahead of print
  14. Finger RP, Schmitz-Valckenberg S, Schmid M, Rubin GS, Dunbar H, Tufail A, Crabb DP, Binns A, Sánchez CI, Margaron P, Normand G, Durbin MK, Luhmann UFO, Zamiri P, Cunha-Vaz J, Asmus F, Holz FG; on behalf of the MACUSTAR consortium. MACUSTAR: Development and Clinical Validation of Functional, Structural, and Patient-Reported Endpoints in Intermediate Age-Related Macular Degeneration. Ophthalmologica. 2019;241(2):61-72
  15. Holz FG, Sadda SR, Busbee B, Chew EY, Mitchell P, Tufail A, Brittain C, Ferrara D, Gray S, Honigberg L, Martin J, Tong B, Ehrlich JS, Bressler NM; Chroma and Spectri Study Investigators. Efficacy and Safety of Lampalizumab for Geographic Atrophy Due to Age-Related Macular Degeneration: Chroma and Spectri Phase 3 Randomized Clinical Trials. JAMA Ophthalmol. 2018 Jun 1;136(6):666-677
  16. 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. PROGNOSTIC VALUE OF SHAPE-DESCRIPTIVE FACTORS FOR THE PROGRESSION OF GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED MACULAR DEGENERATION. Retina. 2019 Aug;39(8):1527-1540
  17. Thiele S, Nadal J, Fleckenstein M, Fang PP, Pfau M, Schmid M, Hua R, Holz FG, Schmitz-Valckenberg S; MODIAMD-Study Group. Longitudinal Analysis of Drusen Volume in Intermediate Age-Related Macular Degeneration Using Two Spectral-Domain Optical Coherence Tomography Scan Patterns. Ophthalmologica. 2018;239(2-3):110-120
  18. Wintergerst MWM, Schultz T, Birtel J, Schuster AK, Pfeiffer N, Schmitz-Valckenberg S, Holz FG, Finger RP. Algorithms for the Automated Analysis of Age-Related Macular Degeneration Biomarkers on Optical Coherence Tomography: A Systematic Review. Transl Vis Sci Technol. 2017 Jul 18;6(4):10
  19. Pfau M, Goerdt L, Schmitz-Valckenberg S, Mauschitz MM, Mishra DK, Holz FG, Lindner M, Fleckenstein M. Green-Light Autofluorescence Versus Combined Blue-Light Autofluorescence and Near-Infrared Reflectance Imaging in Geographic Atrophy Secondary to Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci. 2017 May 1;58(6):BIO121-BIO130
  20. Oishi A, Thiele S, Nadal J, Oishi M, Fleckenstein M, Schmid M, Holz FG, Schmitz-Valckenberg S. Prevalence, Natural Course, and Prognostic Role of Refractile Drusen in Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci. 2017 Apr 1;58(4):2198-2206
  21. Holz FG, Sadda SR, Staurenghi G, Lindner M, Bird AC, Blodi BA, Bottoni F, Chakravarthy U, Chew EY, Csaky K, Curcio CA, Danis R, Fleckenstein M, Freund KB,  Grunwald J, Guymer R, Hoyng CB, Jaffe GJ, Liakopoulos S, Monés JM, Oishi A, Pauleikhoff D, Rosenfeld PJ, Sarraf D, Spaide RF, Tadayoni R, Tufail A, Wolf S, Schmitz-Valckenberg S; CAM group. Imaging Protocols in Clinical Studies in Advanced Age-Related Macular Degeneration: Recommendations from Classification of Atrophy Consensus Meetings. Ophthalmology. 2017 Apr;124(4):464-478
  22. Gliem M, Müller PL, Finger RP, McGuinness MB, Holz FG, Charbel Issa P. Quantitative Fundus Autofluorescence in Early and Intermediate Age-Related Macular Degeneration. JAMA Ophthalmol. 2016 Jul 1;134(7):817-24
  23. Brandstetter C, Patt J, Holz FG, Krohne TU. Inflammasome priming increases retinal pigment epithelial cell susceptibility to lipofuscin phototoxicity by changing the cell death mechanism from apoptosis to pyroptosis. J Photochem Photobiol B. 2016 Aug;161:177-83
  24. Schmitz-Valckenberg S, Göbel AP, Saur SC, Steinberg JS, Thiele S, Wojek C, Russmann C, Holz FG, For The Modiamd-Study Group. Automated Retinal Image Analysis for Evaluation of Focal Hyperpigmentary Changes in Intermediate Age-Related Macular Degeneration. Transl Vis Sci Technol. 2016 Mar 4;5(2):3
  25. Schmitz-Valckenberg S, Sahel JA, Danis R, Fleckenstein M, Jaffe GJ, Wolf S, Pruente C, Holz FG. Natural History of Geographic Atrophy Progression Secondary to Age-Related Macular Degeneration (Geographic Atrophy Progression Study). Ophthalmology. 2016 Feb;123(2):361-8
  26. 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. Directional Kinetics of Geographic Atrophy Progression in Age-Related Macular Degeneration with Foveal Sparing. Ophthalmology. 2015 Jul;122(7):1356-65
  27. Holz FG, Steinberg JS, Göbel A, Fleckenstein M, Schmitz-Valckenberg S. Fundus autofluorescence imaging in dry AMD. Graefes Arch Clin Exp Ophthalmol. 2015 Jan;253(1):7-16
  28. Fleckenstein M, Schmitz-Valckenberg S, Lindner M, Bezatis A, Becker E, Fimmers R, Holz FG; Fundus Autofluorescence in Age-Related Macular Degeneration Study Group. The "diffuse-trickling" fundus autofluorescence phenotype in geographic atrophy. Invest Ophthalmol Vis Sci. 2014 May 2;55(5):2911-20
  29. Holz FG, Strauss EC, Schmitz-Valckenberg S, van Lookeren Campagne M. Geographic atrophy: clinical features and potential therapeutic approaches. Ophthalmology. 2014 May;121(5):1079-91
  30. Schmitz-Valckenberg S, Brinkmann CK, Alten F, Herrmann P, Stratmann NK, Göbel AP, Fleckenstein M, Diller M, Jaffe GJ, Holz FG. Semiautomated image processing method for identification and quantification of geographic atrophy in  age-related macular degeneration. Invest Ophthalmol Vis Sci. 2011 Sep 29;52(10):7640-6
  31. Schmitz-Valckenberg S, Alten F, Steinberg JS, Jaffe GJ, Fleckenstein M, Mukesh BN, Hohman TC, Holz FG; Geographic Atrophy Progression (GAP) Study Group. Reticular drusen associated with geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2011 Aug 24;52(9):5009-15
  32. Scholl HP, Charbel Issa P, Walier M, Janzer S, Pollok-Kopp B, Börncke F, Fritsche LG, Chong NV, Fimmers R, Wienker T, Holz FG, Weber BH, Oppermann M. Systemic complement activation in age-related macular degeneration. PLoS One. 2008 Jul 2;3(7):e2593.
  33. Helb HM, Charbel Issa P, VAN DER Veen RL, Berendschot TT, Scholl HP, Holz FG. Abnormal macular pigment distribution in type 2 idiopathic macular telangiectasia. Retina. 2008 Jun;28(6):808-16
  34. Holz FG, Bindewald-Wittich A, Fleckenstein M, Dreyhaupt J, Scholl HP, Schmitz-Valckenberg S; FAM-Study Group. Progression of geographic atrophy and impact of fundus autofluorescence patterns in age-related macular degeneration. Am J Ophthalmol. 2007 Mar;143(3):463-72
  35. Holz FG, Wolfensberger TJ, Piguet B, Gross-Jendroska M, Wells JA, Minassian  DC, Chisholm IH, Bird AC. Bilateral macular drusen in age-related macular degeneration. Prognosis and risk factors. Ophthalmology. 1994 Sep;101(9):1522-8
Professor Frank G. Holz

Professor Frank G. Holz

FEBO, FARVO

University of Bonn
Deptartment of Ophthalmology
Ernst-Abbe-Straße 2
D-53127 Bonn
Germany

Phone: +49 (0)228 / 287 - 15646
E-mail: Frank.Holz[at]ukbonn.de

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