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Article Reading Performance in Blue Cone Monochromacy: Defining an Outcome Measure for a Clinical Trial Evelyn P. Semenov1, Rebecca Sheplock1, Alejandro J. Roman1, David B. McGuigan1, Malgorzata Swider1, Artur V. Cideciyan1, and Samuel G. Jacobson1 1 Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA Correspondence: Samuel G. Purpose: Blue cone monochromacy (BCM), a congenital X-linked retinal disease caused Jacobson, Scheie Eye Institute, by mutations in the OPN1LW/OPN1MW gene cluster, is under consideration for intrav- University of Pennsylvania, 51 N. itreal gene therapy. Difficulties with near vision tasks experienced by these patients 39th Street, Philadelphia, PA 19104, prompted this study of reading performance as a potential outcome measure for a future USA. e-mail: clinical trial. [email protected] Methods: Clinically and molecularly diagnosed patients with BCM (n = 17; ages Received: July 20, 2020 15–63 years) and subjects with normal vision (n = 22; ages 18–72 years) were examined Accepted: October 12, 2020 with the MNREAD acuity chart for both uniocular and binocular conditions. Parameters Published: December 8, 2020 derived from the measurements in patients were compared with normal data and also Keywords: clinical trial; cone; gene within the group of patients. Intersession, interocular and between-subject variabilities mutations; outcome measure; were determined. The frequent complaint of light sensitivity in BCM was examined by reading; visual acuity comparing results from black text on a white background (regular polarity) versus white on black (reverse polarity) conditions. Citation: Semenov EP, Sheplock R, Roman AJ, McGuigan DB, Swider M, Results: MNREAD curves of print size versus reading speed were right-shifted compared Cideciyan AV, Jacobson SG. Reading with normal in all patients with BCM. All parameters in patients with BCM indicated performance in blue cone abnormal reading performance. Intersession variability was slightly higher in BCM than monochromacy: Defining an in normal, but comparable with results previously reported for other patients with outcome measure for a clinical trial. maculopathies. There was a high degree of disease symmetry in reading performance in Trans Vis Sci Tech. 2020;9(13):13, this BCM cohort. Reverse polarity showed better reading parameters than regular polar- https://doi.org/10.1167/tvst.9.13.13 ity in 82% of the patients. Conclusions: MNREAD measures of reading performance in patients with BCM would be a worthy and robust secondary outcome in a clinical trial protocol, given its dual purpose of quantifying macular vision and addressing an important quality of life issue. Translational Relevance: Assessment of an outcome for a clinical trial. some increase in sensitivity to glare. Diseases of the Introduction macula can be acquired, multifactorial, or inherited.4 Major progress in the diagnosis and treatment of The human macula is defined anatomically as the macular diseases has led to clinical trials that seek retinal region of approximately 6 mm (about 18°) in to test if proposed therapies have both safety and diameter centered on the fovea.1,2 The cone-rich fovea efficacy (e.g., Reference5). A key outcome in such (1.5 mm or 5° diameter) is surrounded by para- and trials has traditionally been best-corrected visual acuity perifoveal retina with an increasing number of rod (BCVA) using Early Treatment Diabetic Retinopa- photoreceptors. At the edge of the macula, the ratio thy Study (ETDRS) methodology to evaluate central reaches about 25 rods for every cone.3 The macula vision.6–8 Evaluation of the macula has become more supports high spatial vision and the central visual field; sophisticated with the advent of newer psychophysical macular disease typically causes symptoms of blurred modalities9–11 and imaging,12–16 and recent trials have and distorted vision, both at distance and near, and added such secondary and exploratory outcomes to Copyright 2020 The Authors tvst.arvojournals.org | ISSN: 2164-2591 1 This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Reading in BCM TVST | December 2020 | Vol. 9 | No. 13 | Article 13 | 2 protocols. Further, there is an emphasis on assays of quality of life with instruments such as National Eye Methods Institute Visual Function Questionnaire,17 and these are commonly used in protocols (e.g., Reference18). Human Subjects The most frequent target of research and treat- The study included 17 patients with BCM (median ment initiatives for macular disease continues to age, 34 years; range, 15–63 years) and 22 subjects be age-related macular degeneration (AMD), the 19 with normal vision (median age, 30 years; range, 18– leading cause of central vision loss in later life. 72 years). Patients had a clinical and molecular diagno- The less common “juvenile macular degenera- sis of BCM (Table 1). Molecular testing of the patients tions” have now entered the era of gene discov- and their families has been previously reported.25,27,28 ery and many of these inherited retinal degenera- No study participants reported cognitive impairment tions (IRDs) have molecular diagnoses and disease or reading disability (dyslexia) and all participants mechanisms that are much better understood. This were native or fluent English speakers. Normal subjects progress has led to gene-based therapies in these had 20/25 or better BCVA in each eye. Procedures previously incurable IRDs, with early manifes- followed the Declaration of Helsinki and the study was tation of macular dysfunction or degeneration. approved by the University of Pennsylvania Institu- For example, Stargardt disease caused by biallelic tional Review Board. Informed consent was obtained mutations in the ABCA4 gene is one of the more from adults, and assent with parental permission from common IRDs with pronounced maculopathy. A children. All patients previously had a complete eye multitude of non–gene- and gene-based therapies have 19 examination (median time since previous visit, 3 years; been attempted to date. Recently, two genotypes range, 2–7 years). (CNGA3, CNGB3) of achromatopsia (ACHM), a heterogeneous group of autosomal recessive IRDs with congenital retina-wide cone photoreceptor Instrumentation and Testing Procedures disease and maculopathy, have received or are under- going treatment with subretinal gene augmenta- Reading performance was measured using the tion therapy (NCT02610582, NCT03758404, and MNREAD iPad application (Calabrese A, et al. NCT04124185).20,21 IOVS. 2014;55:ARVO E-Abstract 5601).29 Testing was Another IRD with retina-wide cone photorecep- performed using an iPad Pro with 12.9” Liquid Retina tor disease that causes congenital macular dysfunc- Display (2732 × 2048 pixels, 264 pixels per inch resolu- tion and can lead to macular degeneration is being tion). Screen luminance was set to 75%29 and kept considered for gene augmentation therapy. Blue cone constant for all testing conditions. Under this setting, monochromacy (BCM) is an X-linked disease caused average measured luminance was 277 phot-cd.m−2.For by mutations in the OPN1LW/OPN1MW gene cluster, all reading tests, the iPad was positioned in landscape resulting in impaired long (L) and middle (M) orientation at a fixed distance of 40 cm between the wavelength-sensitive cone photoreceptor function.22–26 subject’s eyes and the middle of the iPad screen29–31 Among the visual complaints of patients with BCM using a combination of an adjustable height tablet are impaired visual acuity, color vision abnormal- stand and an attached fixed-distance chin rest. The ities, and sensitivity to light.27 In an early phase height of the iPad stand was adjusted for each subject clinical trial, the primary goal would be to assess so the center of the iPad screen was at eye level to safety of the therapy and the clinical eye exami- ensure accurate sentence presentation.29 nation with imaging of the retina would be a Subjects were tested in their homes using a testing primary outcome. The conventional outcome measure kit mailed to their residence after they agreed to partic- of macular function, BCVA, would serve as both ipate and signed a consent and/or assent. The testing a safety assay and an early gauge of efficacy. We package included an iPad, an iPad stand, a chin rest, sought a further efficacy measure to quantify the and an instruction manual. All subjects were instructed visual symptoms of BCM and also serve as a to complete testing in a dimly lit environment away method to understand the impact of the disease from potential sources of screen reflections and glare and therapy on quality of life. Because difficulty in and they were given time to adjust to room lighting. reading is a notable patient complaint in BCM, we Each test session was directed and supervised in its explored in detail how reading vision performance entirety by one author (E.S. or R.S.) over the telephone. is impaired, what parameters would be most helpful A practice test was conducted before the first session as outcomes in a clinical trial, and their variability using the practice chart feature of the application after characteristics. verbal confirmation that the ambient conditions were Reading in BCM Table 1. Characteristics of Patients with BCM Visual Acuity* Correction Worn for MNRead‡ PatientNo. AgeatTest OPN1MW/OPN1LW Gene Cluster Mutation Right Left Right Left IS/OS Defect Extent (°)¶ Patient
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