Visual Function Metrics in Early and Intermediate Dry Age-related Macular Degeneration for Use as Clinical Trial Endpoints

Age related macular degeneration (AMD) is the most common cause of blindness, accounting for 8.7% of all blindness globally. Vision loss is caused ultimately by apoptosis of the retinal pigment epithelium (RPE) and overlying photoreceptors. Treatments are evolving for the wet form of the disease, however these do not exist for the dry form. Complement factor H (CFH) polymorphism in exon 9 (Y402H) has shown a strong association with susceptibility to AMD resulting in complement activation, recruitment of phagocytes, retinal pigment epithelium (RPE) damage and visual decline. We have derived and characterised induced pluripotent stem cell (iPSCs) lines from two patients without AMD and low risk genotype and two patients with advanced AMD and high risk genotype and generated RPE cells that show local secretion of several proteins involved in the complement pathway including factor H (FH), factor I (FI) and factor H like 1 (FHL-1). The iPSC RPE cells derived from high risk patients mimic several key features of AMD including increased inflammation and cellular stress, accumulation of lipid droplets, impaired autophagy and deposition of “drusen” like deposits. The low and high risk RPE cells respond differently to intermittent exposure to UV light which leads to an improvement in cellular and functional phenotype only in the high risk AMD-RPE cells. Taken together our data indicate that the patient specific iPSC model provides a robust platform for understanding the role of complement activation in AMD, evaluating new therapies based on complement modulation and drug testing. This article is protected by copyright. All rights reserved.

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An Induced Pluripotent Stem Cell Patient Specific Model of Complement Factor H (Y402H) Polymorphism Displays Characteristic Features of Age-Related Macular Degeneration and Indicates a Beneficial Role for UV Light Exposure

Age-related macular degeneration (AMD) is one of the major causes of visual loss and legal blindness in people over 55. Visual function tests are the cornerstone of visual function investigation and any therapeutic approach to AMD implies, as primary endpoint, the maintenance or improvement of visual function. The progression of visual impairment and the quantification of final residual visual function are currently determined by means of visual acuity quantification. The quantification of high-contrast visual acuity though has many drawbacks and cannot be considered a complete functional examination. Microperimetry is a non-invasive method used to analyse fixation and central visual field defects in a topographic related manner. The introduction of mesopic and more recently scotopic microperimetry, in research and clinical practice of macular disorders, now allows us to better investigate macular function as it strictly relates to macular morphology. We therefore can monitor the functional natural history and quantify the beneficial or detrimental effects of different therapies. The application of microperimetry in clinical studies has provided interesting diagnostic and prognostic information on functional macular changes in AMD patients. The present review brings new updates on the correlation between macular changes, mainly described with optical coherence tomography, and microperimetry changes in patients with AMD.

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Microperimetry in age: related macular degeneration.

The use of microperimetry in assessing visual function in age-related macular degeneration.

Purpose To determine the intrasession test-retest reliability of mesopic and dark-adapted fundus-controlled perimetry in patients with intermediate age-related macular degeneration (iAMD). Methods We conducted a cross-sectional study with 23 iAMD patients (67.3 ± 8.2 years; range, 50-85; 78% female) and 24 healthy controls (61.3 ± 5.2 years; range, 50-71; 50% female) using a modified MAIA microperimeter. All patients underwent duplicate mesopic (achromatic stimuli, 400-800 nm) and dark-adapted (red stimuli, 627 nm) microperimetry, using a grid of 33 stimuli over 14° of the central retina. Main outcome measure was the intrasession test-retest reliability for pointwise sensitivity (PWS). Results PWS test-retest reliability was good among mesopic and dark-adapted testing in both patients and controls (coefficient of repeatability of 4.4, 4.52, 3.96, and 4.56 dB, respectively). Mean mesopic sensitivity in patients was 2.62 dB lower than in controls (P < 0.01); mean dark-adapted sensitivity was 2.49 dB lower than in controls (P < 0.01). Conclusions The modified MAIA device allows for reliable mesopic and dark-adapted microperimetry in iAMD patients. We found that iAMD is associated with both reduced mesopic and dark-adapted retinal sensitivity.

Retest Reliability of Mesopic and Dark-Adapted Microperimetry in Patients With Intermediate Age-Related Macular Degeneration and Age-Matched Controls

PURPOSE The objectives of this study were to evaluate 1) the feasibility of performing computerized tests of low luminance visual acuity (LLVA), cone-specific contrast (Cone Contrast Test [CCT]), contrast sensitivity, and microperimetry and 2) the test-retest repeatability of these outcomes in dry age-related macular degeneration (AMD). METHODS This prospective study enrolled 30 subjects at a single site (8 controls, 8 early AMD, and 12 intermediate AMD). Subjects underwent LLVA, contrast sensitivity, CCT, and microperimetry with eye tracking. Low luminance deficit was defined as best-corrected visual acuity minus LLVA in EDTRS letters. Follow-up testing was administered at approximately 1 month. RESULTS There was high test-retest repeatability at one month for all visual function metrics (intraclass correlations >0.7) except log contrast sensitivity (intraclass correlations 0.6). Compared with controls, patients with intermediate AMD showed significant deficits on best-corrected visual acuity, LLVA, low luminance deficit, percent-reduced threshold on microperimetry, and red CCT (P < 0.05), but not on contrast sensitivity, green and blue CCT. CONCLUSION This pilot study supports the feasibility and reliability of using LLVA, microperimetry, and CCT in early dry AMD. Our data suggest these measures can be used as alternative future clinical trial endpoints. A larger, prospective natural history study of alternative visual function measures in dry AMD is warranted.

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John T. Petrowski

Papers

Visual function measures in early and intermediate age-related macular degeneration.