Rare Inherited Retinal Disorders: Challenges and Consortium Model

Overview Last Updated: March 7, 2025

Retinal Degenerations Rare: less common than 1:3,500 worldwide Inherited: families may be concentrated in areas with limited access to specialist care Extreme genetic heterogeneity: caused by genetic changes in over 300 genes, with variable and widely ranging clinical manifestations associated with each gene Relentless: genetic changes cause progressive dysfunction and death of rod and cone photoreceptors No effective treatments for most

Challenges to Developing Treatments Uncommon: few patients available for study, limited information exists Wide range of phenotypes requires evaluation using specialty testing and expert clinical evaluation Limited standardized prospective natural history data on IRDs Unclear what outcome measures will be most likely to demonstrate change over time, or safety and efficacy of treatments

Mission Statement The Foundation seeks to build a Consortium for the purpose of conducting clinical studies in patients with rare inherited retinal disorders (IRDs). The goal is to accelerate the development of treatments for IRDs. To accomplish this, the Foundation plans to build centers of excellence to participate in sponsored clinical studies. Investigators from participating clinical centers will collaborate on ideas for hypotheses, study designs, analysis plans, and publications. Data from the completed trials will be archived in an open central repository to stimulate further hypothesis generation and innovation.

Consortium Model Goal: Accelerate development of treatments for IRDs Investigators collaborate on ideas for hypotheses, study designs, and publications Consortium Natural History Studies (NHS): Provide prospective, standardized, longitudinal data on disease progression Identify sensitive structural and functional outcome measures for future clinical trials Data from completed studies will be archived in an open central repository to stimulate further hypothesis generation and innovation

Organizational Structure Foundation Fighting Blindness Scientific Advisory Board Executive Committee Multidisciplinary Experts Duke Reading Center Casey Reading Center Genetics Committee InformedDNA (Central Genetics Auditor) Veriome (Variant Analysis) EMMES (VA Testing) Streetlab (MOST-VR) KKI, JHU (GYROS Central Labs) Coordinating Center Jaeb Center for Health Research Operations Committee Clinical Sites

Allison Ayala Project Director Research Operations Jennifer Shah Research Operations Manager Michelle Slawiak Research Operations Assistant Protocols Abagail Ault Protocol Manager - RUSH1F, GYROS, Pro-EYS Ruth Thomas Protocol Manager - Uni-Rare, RUSH2A Liz Caruana Research Manager Coordinating Center Team Tiffany Swinford Protocol Monitor Kay Sorhaindo Protocol Monitor Axelie Castillo Protocol Research Assistant Analysis, Publications and Datasets Sara Hatch Publications Manager Michele Melia Senior Statistician Wei Tian Senior Statistician Yu-Fen Li Statistician Wendi Liang Statistician Lee McDaniel Statistician Lassana Samarakoon Statistician Database and Development Stephanie Lee, Nadine LaBell, Evan Gilbert

Oversight and Leadership Operations Committee Genetics Committee Executive Committee Jacque Duncan Kari Branham (Chair) Jacque Duncan (Co-Chair) Rachel Huckfeldt (Co-Chair) Rachel Huckfeldt Rob Hufnagel Allison Ayala Allison Ayala Juliana Sallum Janet Cheetham Janet Cheetham Todd Durham Todd Durham Rick Ferris Michel Michaelides Mark Pennesi Jos -Alain Sahel

University of Michigan, Kellogg Eye Center Oregon Health & Science Univ., Casey Eye Institute Baylor College of Medicine, Alkek Eye Center Emory University, Emory Eye Center Ghent University Harvard Univ., Massachusetts Eye and Ear Infirmary Medical College of Wisconsin Eye Institute Moorfields Eye Hospital National Eye Institute CHNO des Quinze-Vingts Radboud University Medical Center Retina Foundation of the Southwest University of California San Francisco University of Toronto, Hospital for Sick Children University of Tuebingen, Centre for Ophthalmology University of Utah, John Moran Eye Center Vitreo Retinal Associates Johns Hopkins University, Wilmer Eye Institute Duke University, Duke Eye Center Colorado Retina Associates University of Arkansas, Jones Eye Institute University of Miami, Bascom Palmer Eye Institute University of Wisconsin Madison Associated Retina Consultants Univ. of California San Diego,Jacobs Retina Center Helsinki University Hospital Hadassah-Hebrew University Medical Center UPMC Eye Center Instituto de Gen tica Ocular University of Pennsylvania INRET Cl nica e Centro de Pesquisa University Hospital Basel (USB) University of Florida Health Jacksonville Retina and Genomics Institute University of Alberta and Alberta Health Services Centre for Eye Research Australia Mayo Clinic University Hospital Jules-Gonin Vista Vision Eye Clinic University Health Network Oslo University Hospital USC Roski Eye Institute Amsterdam University Medical Centers Clinical Sites 43 Sites 15 Countries

FFB Consortium Members Total Sites 43 Investigators 137 Coordinators 150 Technicians 268

Consortium Strengths Feasible recruitment Due to large number of international sites Data quality Enforced by standardized procedures Efficiencies Gained from existing infrastructure Collaboration Of ideas and expertise from multidisciplinary team Sharing Of datasets further our mission to advance IRD research

Consortium Efficiencies Master Agreements IRB Reliance Agreements Technician Certification Standardized Data Collection Forms Standardized Procedures Downstream efficiencies monitoring procedures, reports, checks and statistical coding become standardized and based on templates

Objectives of our NHS Estimate rates of progression Investigate structure-function relationships Explore properties of candidate endpoints (e.g., signal-to- noise, reproducibility, symmetry) Identify factors related to progression Define genotype-phenotype associations Provide a source of historical control data Inform the design and practical challenges of clinical trials

Outcome Measures in our NHS Structural Spectral-domain optical coherence tomography EZ area, fundus autofluorescence Functional Static perimetry, microperimetry, full-field stimulus threshold, electroretinography, visual acuity, contrast sensitivity, color vision Patient-reported outcomes Visual function questionnaires and quality-of-life questionnaires

Studies

Clinical Consortium NHS to Date Study Details #1 - Rate of Progression in USH2A- related Retinal Degeneration (RUSH2A) Study Chair: Jacque Duncan, MD Final Sample Size: 127 participants Status: 4-yr follow-up completed 2023, 7- and 9-yr extension in progress #2 - Rate of Progression in EYS-related Retinal Degeneration (Pro-EYS) Study Chair: Mark Pennesi, MD, PhD Final Sample Size: 103 participants Status: 4-yr follow-up to be completed December 2025 #3 - Rate of Progression of PCDH15- related Retinal Degeneration in Usher Syndrome 1F (RUSH1F)* Study Chair: Katarina Stingl, MD Final Sample Size: 44 participants Status: Recruitment completed 2023, 4-yr follow-up to be completed 2027 #4 Gyrate Atrophy Ocular and Systemic Study (GYROS) Study Co-Chairs: Mandeep Singh, MD and David Valle, MD Sample Size Goal: 45 participants Status: Recruitment to be completed 2025, 4-yr follow-up to be completed 2028 #5 Universal Rare Gene Study (Uni-Rare) Study Chair: Jose-Alain Sahel, MD Sample Size Goal: 1500 participants (Registry); gene-by-gene goals for NHSs Status: Recruitment ongoing *Co-funded by FFB, Usher 1F Collaborative & Marjorie C. Adams Foundation Co-funded by FFB, Conquering Gyrate Atrophy, and FDA This project is supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award R01FD007628 totaling $1.6M with 46% funded by FDA/HHS and $1.9M and 54% funded by non-government source(s). The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, or the U.S. Government. Co-funded by Foundation Fighting Blindness, BlueRock Therapeutics, Opus Genetics, Atsena Therapeutics, Cove Therapeutics, Save Sight Now, Maryrose Sylvester, Anonymous Donor, Sarah de Coizart Trust, Max and Minnie Tomerlin Voelcker Fund, Usher III Initiative.

Rate of Progression in USH2A-related Retinal Degeneration (RUSH2A) Study Chair: Jacque Duncan Design: 4-year natural history study; 7- and 9-year extension Objectives: 1. Characterize the natural history of USH2A-related retinal degeneration 2. Investigate structure-function relationships 3. Evaluate possible risk factors (genotype, phenotype, environmental, and comorbidities) for progression of the outcome measures 4. Evaluate variability (test-retest) and symmetry (left vs right eye) of select outcomes Final Sample Size: 127 participants Funded by FFB Status: 4-year follow-up completed in 2023; 7-year follow-up to be completed in 2026 NCT03146078

Rate of Progression in EYS-related Retinal Degeneration (Pro-EYS) Study Chair: Mark Pennesi Design: 4-year natural history study Objectives: 1. Characterize the natural history of retinal degeneration associated with EYS 2. Investigate structure-function relationships 3. Evaluate possible risk factors (genotype, phenotype, environmental, and comorbidities) for progression of outcome measures 4. Evaluate variability (test-retest) and symmetry (left vs right eye) of select outcomes Final Sample Size: 103 participants Funded by FFB Status: Concluded recruitment in 2021, 4-year follow-up to be completed in 2025 NCT04127006

Rate of Progression of PCDH15-related Retinal Degeneration in Usher Syndrome 1F (RUSH1F) Study Chair: Katarina Stingl Design: 4-year natural history study Objectives: 1. Characterize the natural history of PCDH15-related retinal degeneration 2. Investigate structure-function relationships 3. Evaluate possible risk factors for progression of outcome measures 4. Evaluate variability and symmetry of select outcomes Final Sample Size: 44 participants Co-funded:FFB, Usher 1F Collaborative & Marjorie C. Adams Foundation Status: Recruitment completed 2023, 4-year follow-up to be completed in 2027 NCT04765345

Gyrate Atrophy Ocular and Systemic Study (GYROS) Study Chairs: Mandeep Singh & David Valle Design: 4-year natural history study Objectives: 1. Characterize the natural history of retinal degeneration (RD) structural and functional measures and metabolic features 2. Explore metabolic structure-function relationships RD measures and plasma ornithine levels 3. Explore factors that contribute to rate of progression Sample Size Goal: 45 participants Co-funded: FFB, Conquering Gyrate Atrophy & FDA OOPD Grant This project is supported by the FDA of the U.S. Department of HHS as part of a financial assistance award R01FD007628 totaling $1.6M with 46% funded by FDA/HHS and $1.9M and 54% funded by non-government sources. The contents are those of the authors and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, or the U.S. Government Status: Recruitment completed 2025; 4-year follow-up to be completed end of 2028 NCT05312736

Universal Rare Gene Study (Uni-Rare) Study Chair: Jos -Alain Sahel Registry Component Prospective, standardized, cross- sectional clinical data collection Open to >300 rare IRD genes N=1500 Natural History Study (NHS) Component Prospective, standardized, longitudinal (4 years) clinical data collection A platform to move participants from the registry as each gene opens N=100 cap per gene Genotype Characterization Cross-Sectional Phenotype Characterization Natural History using Functional, Structural, PRO Measures Structure-Function Relationship Risk Factors for Progression Co-funded: FFB, Opus Genetics, Atsena Therapeutics, BlueRock Therapeutics, Cove Therapeutics, Save Sight Now, Maryrose Sylvester, Anonymous Donor, Sarah de Coizart Trust, Max and Minnie Tomerlin Voelcker Fund, Usher III Initiative Status: Enrollment began May 2023; Registry recruitment end goal December 2025 NCT05589714

Uni-Rare Impact Part 1 Cross-sectional registry The registry will establish genetically and clinically well-characterized cohorts of patients across hundreds of genetic variants associated with retinal dystrophy. Characterization of these patients will: Provide cross-sectional data on phenotype- genotype associations Contribute to our knowledge of pathogenicity of these rare disease-causing variants Accelerate eligibility screening for subsequent natural history studies Part 2 Prospective, natural history The natural history study will accelerate the identification of sensitive, reliable outcome measures for clinical trials, which will facilitate development of treatments for retinal dystrophies due to disease-causing genetic variants. The expected impact of the natural history study is to: Describe the natural history of retinal degeneration in patients with rare disease-causing genetic variants Define sensitive structural and functional outcome measures for future multicenter clinical trials of rare inherited retinal degeneration Identify well-defined subpopulations for future clinical trials of treatments for rare inherited retinal degeneration

Annual Gene Poll Database Created to capture an annual snapshot of the number of patients with disease-causing variants in all known IRD genes (>300), across all Clinical Consortium sites Also includes a survey on practices surrounding clinical and genetic testing at each Consortium site First annual poll was initiated in 2020

Manuscripts and Presentations

General Consortium Manuscripts Topic Lead Author* Journal Status FFB Consortium Consortium Background Todd Durham TVST 2021 FFB Consortium FFB Gene Poll Kari Branham IOVS 2025 *for the FFB Clinical Consortium Investigator Group

General Consortium Presentations Topic Presenter* Conference FFB Consortium Background Jacque Duncan Janet Cheetham Mark Pennesi Jacque Duncan Jacque Duncan Allison Ayala Mandeep Singh Rachel Huckfeldt Rachel Huckfeldt Todd Durham Jacque Duncan Macula Society 2020 ARVO 2020 ISGEDR 2021 ARVO 2022 AAO 2022 ERN-EYE 2022 APAO 2023 ISGEDR 2023 Johns Hopkins RD&VE Conf, 2023 Gene Therapy for Ophth Disorders 2023 RD 2023 MP and SP Tolerance Limits Allison Ayala Wendi Liang ARVO 2020 SCT 2020 2020 Gene Poll Kari Branham Kari Branham ISGEDR 2021 UPMC 2023 *for the FFB Clinical Consortium Investigator Group

REDI Working Group Manuscripts Topic Lead Author* Journal Status REDI RUSH2A Endpoints Maureen Maguire TVST 2024 *for the FFB Clinical Consortium Investigator Group

REDI Working Group Presentations Topic Presenter* Conference REDI - Endpoints and Trial Design Maureen Maguire Jacque Duncan and Rachel Huckfeldt Multiple Presenters Johns Hopkins RD&VE Conf 2023 ARVO Symposium 2025 - Pending ARVO SIG 2025 Submitted REDI-1 (RUSH2A Endpoints) Rachel Huckfeldt Jacque Duncan Rachel Huckfeldt Jos Alain-Sahel Multiple Presenters Rachel Huckfeldt Jacque Duncan Rachel Huckfeldt Rachel Huckfeldt Jacque Duncan RD 2023 FFB Innovations Summit 2023 Macula Society 2024 Young Hadassah Eye & Vision 2024 ARVO Special Session 2024 ERN-EYE 2024 ODF2 2024 Mary Tyler Moore Vision Initiative 2024 ARVO Frontiers in Ocular GT Res 2024 FFB Innovations Summit 2025 Pending REDI-2 (FTPs) Rachel Huckfeldt Allison Ayala Lee McDaniel Macula Society 2025 ERN-EYE 2024 ARVO 2025 Pending REDI-5 (FST Data Rev) David Birch David Birch ERN-EYE 2024 ODF2 2024 Rachel Huckfeldt, David Birch, Jacque Duncan, Todd Durham Rachel Huckfeldt, Jacque Duncan, Ajoy Vincent, Eleonora Lad, David Birch, Thiran Jayasundera, and Allison Ayala *for the FFB Clinical Consortium Investigator Group

RUSH2A Manuscripts Topic Lead Author* Journal Status RUSH2A-1 (Baseline SP, KP) Jacque Duncan AJO 2020 RUSH2A-3 (Baseline Genetics) Robert Hufnagel Human Mutation 2022 RUSH2A-4 (Baseline MP, OCT) Eleonora Lad AJO 2022 RUSH2A-5 (Baseline VA, ERG, FST) David Birch TVST 2020 RUSH2A-6 (Baseline PROs) Elise Heon AJO 2023 RUSH2A-7 (BL to 48M SP-OCT Overlay) Mark Pennesi Working RUSH2A-8 (Baseline Olfactory/Audiology) Alessandro Iannaccone AJMG 2021 RUSH2A-9 (Baseline-24M AOSLO) Jacque Duncan AJO 2023 RUSH2A-10 (Baseline DAVF) David Birch IOVS 2022 RUSH2A-11 (24M SP) Jacque Duncan AJO 2023 RUSH2A-14 (48M SP/KP) Jacque Duncan AJO (In Press) RUSH2A-17 (48M MP OCT) Ajoy Vincent AJO (In Press) RUSH2A-18 (48M VA FST ERG) David Birch Ophthalmology Science 2024 RUSH2A-19 (48M PRO VALVVFQ48) Bela Parekh IOVS (In Press) RUSH2A-20 (48M PRO MRDQ) Bela Parekh IOVS 2024 *for the FFB Clinical Consortium Investigator Group RUSH2A-21 (36M DAVF) David Birch Working

RUSH2A Presentations Topic Presenter* Conference RUSH2A-1 (Baseline SP, KP) Jacque Duncan ARVO 2020 RUSH2A-3 (Baseline Genetics) Robert Hufnagel ARVO 2020, ISGEDR 2021, ASHG 2021, APAO 2023, JH RD&VE Conf 2023 RUSH2A-4 (Baseline MP, OCT) Christine Kay Eleonora Lad Retina Society 2020 Macula Society 2021, ARVO 2021 RUSH2A-6 (Baseline PROs) Elise Heon ARVO 2020 RUSH2A-7 (SP OCT Overlay) Audra Miller ARVO 2024 RUSH2A-8 (Baseline Olfactory/Audiology) Alessandro Iannaccone ARVO 2021 RUSH2A-9 (Baseline [24M] AOSLO) Jacque Duncan ARVO 2021, RD 2021, ARVO 2023 RUSH2A-10 (Baseline DAVF) David Birch ARVO 2021, FFB Innovations Summit 2023 RUSH2A-11 (24M SP) Jacque Duncan Mark Pennesi ARVO 2022 Retina Society 2022 RUSH2A-12 (24M VA, FST) Peiyao Cheng ARVO 2022 RUSH2A-13 (24M MP, OCT) Ajoy Vincent Eleonora Lad ARVO 2022 Hawaiian Eye & Retina 2023 *for the FFB Clinical Consortium Investigator Group

Pro-EYS Presentations Topic Presenter* Conference Pro-EYS-1 (BL SP) Rachel Huckfeldt ARVO 2023 Pro-EYS-2 (BL MP/OCT/OCT-VH) David Birch ARVO 2023 Pro-EYS-3 (BL VA/FST/ERG/CS) Ajoy Vincent ARVO 2023 Pro-EYS-4 (BL FAF Optos vs Spectralis) Nieraj Jain ARVO 2023 Pro-EYS-5 (BL-PRO) Brett Malbin ARVO 2023 Bin Guan Rob Hufnagel ARVO 2023 ISGEDR 2023 Pro-EYS-6 (BL Genetics) Pro-EYS Study and Baseline Overview Rachel Huckfeldt FFB Innovations Summit 2023 *for the FFB Clinical Consortium Investigator Group

RUSH1F Presentations Topic Presenter* Conference RUSH1F Study Overview Katarina Stingl Usher 1F Virtual Conference 2022 *for the FFB Clinical Consortium Investigator Group

Uni-Rare Presentations Topic Presenter* Conference Uni-Rare Study Overview Jos -Alain Sahel Rachel Huckfeldt Todd Durham Ocular Disease Forum 2023 RDH12 2023 ARVO SIG 2023 *for the FFB Clinical Consortium Investigator Group

GYROS Presentations Topic Presenter* Conference GYROS Study Overview Mandeep Singh and David Valle Amsterdam Spinoza Lectures 2023 David Valle Radboud U Med Ctr 2023 David Valle U Amsterdam 2023 David Valle Mexican Symposium GA 2024 Mandeep Singh Pt Foundation, Mexico City 2024 *for the FFB Clinical Consortium Investigator Group

Results Summaries

FFB Consortium 2 Manuscript Characterizing the genetic basis for inherited retinal disease: Lessons learned from the Foundation Fighting Blindness Clinical Consortium s Gene Poll FFB Clinical Consortium centers were polled to identify per-case IRD genetic causality from a list of 387 syndromic and non-syndromic IRD genes Thirty centers responded and reported genetic data from 33,834 patients (27,561 families). Disease-causing variants were reported in 293/387 genes. The most common genetic etiologies were ABCA4 (17%), USH2A (9%), RPGR (6%), PRPH2 (5%), and RHO (4%). The top 100 genes accounted for the genetic cause of disease in 94.4% of patients. This report provides the largest assessment of genetic causality in the IRD patient population across multiple continents to date.

REDI - 1 Manuscript Endpoints and Design for Clinical Trials in USH2A-related Retinal Degeneration: Results and Recommendations from the RUSH2A Natural History Study NHS data from the RUSH2A study identified several outcome measures with good properties for clinical trials, including mean sensitivity (microperimetry and static perimetry) and FST. The highest 4-year proportions of eyes exceeding the CoR were from FST testing (47%) and microperimetry (32%). Specification of loci as functional transition points (FTPs) resulted in 45% (static perimetry) and 46% (microperimetry) at 4 years meeting FDA guidelines for progression. These results may affect clinical trial design for USH2A-related retinal degeneration.

RUSH2A 1 Manuscript Baseline Visual Field Findings in the RUSH2A Study: Associated Factors and Correlation with Other Measures of Disease Severity Participants with USH2A-related Usher syndrome had more severe visual field loss than the non-syndromic ARRP group VTOT was highly reproducible and strongly correlated with other functional and structural measures VTOT may be a useful outcome measure of disease severity in patients with USH2A-related retinal degeneration

RUSH2A 3 Manuscript A tissue-specific allelic hierarchy predicts phenotypic findings for USH2A-related disorders in the RUSH2A study USH2A truncating alleles were associated with USH2 and had a dose-dependent effect on hearing loss severity with no effect on visual loss severity within the USH2 subgroup. A group of missense alleles in an inter-fibronectin domain appeared to be hypomorphic in ARRP. These alleles were associated with later age of onset, larger visual field area, better sensitivity thresholds, and better electroretinographic responses. No effect of genotype on the severity of olfactory deficits was observed. This study unveils a unique, tissue-specific USH2A allelic hierarchy with important prognostic implications for patient counseling and treatment trial endpoints. These findings may inform clinical care or research approaches in others with allelic disorders or pleiotropic phenotypes.

RUSH2A 4 Manuscript Baseline Microperimetry and OCT in the RUSH2A Study: Structure- Function Association and Correlation with Disease Severity Longer disease duration correlated with more severe retinal structure and function abnormalities. There were associations between MP and OCT metrics. Monitoring changes in retinal structure-function relationships during disease progression will provide insights into disease mechanism in USH2A-related retinal degeneration The information on test-retest repeatability have key implications in the design of future therapeutic clinical studies of USH2A-related retinal degeneration. The genotype-phenotype correlations will provide valuable information to guide consideration of the best patient populations to include in early phase treatment trials.

RUSH2A 5 Manuscript The RUSH2A Study: Best-Corrected Visual Acuity, Full-Field Electroretinography Amplitudes and Full-Field Stimulus Thresholds at Baseline Most participants retained good BCVA, consistent with previous studies Lower BCVA letter scores and higher white FST thresholds were significantly associated with longer duration of disease Both ERG and FST measures were significantly worse in USH2 than ARRP, BCVA letter scores in USH2 were only marginally lower ~50% of the entire cohort had unmeasurable rod ERG, limiting its use in clinical trials; cone ERG was less affected

RUSH2A 6 Manuscript Functional Vision in Patients with Bi-allelic USH2A Variants Describe functional vision (FV) and investigate the relationship between FV, visual acuity (VA) and hill of vision (VTOT) at baseline in patients with bi-allelic USH2A variants. Modified VALVVFQ-48 was administered verbally to participants 18 years old. VA was measured in both eyes; VTOT was determined from static perimetry in the study eye (better VA). FV scores were calculated using Rasch analysis ARRP and USH2 participants reported similar functional vision. Overall FV score was moderately correlated with VA and visual field hill of vision. The VALVVFQ-48 was not specific to functional problems of ARRP and USH2 The VALVVFQ-48 not ideal for detecting the impact of USH2A-associated retinal degenerations on activities of daily living

RUSH2A 8 Manuscript Auditory and olfactory findings in patients with USH2A-related retinal degeneration Findings at baseline from the rate of progression in USH2A-related retinal degeneration natural degeneration natural history study (RUSH2A) Hearing loss observed previously in patients with USH2A-related USH2 ranged from mild to severe Sensorineural, bilaterally symmetrical, and gently down-sloping from low to high frequencies The 4F-PTAs in ARRP group show hearing thresholds are slightly elevated above age- and gender-based normative levels Suggesting that there may be a subtle effect of USH2A mutations on the auditory system Results of newborn hearing screenings suggest that hearing loss may be present at birth in some and that it may have a delayed onset in others with USH2A mutations Neither olfaction nor SNHL parameters were significantly associated with age, sex, race/ethnicity or smoking status at study baseline With the exception that age was significantly associated with 4F-PTAs in ARRP participants Olfaction was not associated with any visual measures or hearing Olfaction was not significantly worse than age- and gender-controlled normal population

RUSH2A 9 Manuscript Change in cone structure over 24 months in USH2A-related retinal degeneration Describe cone structure changes using adaptive optics scanning laser ophthalmoscopy (AOSLO) There was variability among graders, which was greater in images with lower image quality. Cone spacing was significantly correlated with eccentricity, quality score and disease duration. On average, the cone spacing Z-score increased 0.14 annually (~9%, P < 0.001) No significant differences in rate of change between disease type (USH2 VS ARRP), site, or grader

RUSH2A 10 Manuscript The RUSH2A Study: Dark-Adapted Visual Fields (DAVF) in patients with retinal degeneration associated with biallelic variants in the USH2A gene Two-color dark-adapted perimetry reliably identifies rod-mediated function in the majority of patients with USH2A mutations, even though many show no evidence of rod ERG function There was a tendency for a higher percentage of participants with ARRP than with USH2 to retain measurable DAVF Maximum rod sensitivity from DAVF is highly (inversely) correlated with FST sensitivity, consistent with both measuring the most sensitive region The volume of the rod Hill of Vision reflects both the topography and the extent of remaining rod function

RUSH2A 11 Manuscript Static Perimetry in the Rate of Progression in USH2A-related Retinal Degeneration (RUSH2A) Study: Assessment through Two Years Significant rates of decline in all 4 SP metrics (VTOT, VPERIPH, V30 and Mean Sensitivity) over 24 months Strong internal correlation among SP measures 4 Year data will be helpful (improve signal to noise less variability around estimates of rates of change)

RUSH2A 18 Manuscript Visual acuity, full-field stimulus thresholds and electroretinography for 4 years in USH2A-associated retinal degeneration RUSH2A study FST showed significant decrease over 4 years with no floor effect, good reproducibility, low CoR; FST Blue correlated with changes in MP MS BCVA is not a sensitive measure of progression in USH2A patients over a 4-year period FST declined significantly over 4 years in USH2A-related retinal degeneration FST may provide a useful measure of vision loss in USH2A-related retinal degeneration We intend to bring participants back at 7 and 9 years to determine whether FST predicts future difficulties with activities of daily living

RUSH2A 20 Manuscript Self-reported functional vision in USH2A-associated retinal degeneration as measured by the Michigan Retinal Degeneration Questionnaire Evaluate self-reported functional vision (FV) and the impact of vision loss in patients with USH2A-associated retinal degeneration using a patient- reported outcome (PRO) measure, the Michigan Retinal Degeneration Questionnaire (MRDQ). RUSH2A participants had least difficulty with activities requiring central vision and most difficulty with activities requiring scotopic and mesopic vision Many MRDQ domains have significant correlations with other visual measures MRDQ shows promise as a reliable and sensitive measure of patient reported outcomes in IRD

Where to Find Results of Clinical Consortium Studies All publications are listed under the PUBLICATIONS tab of the public website (ffb.jaeb.org) Summary slides of all publications are available under the PRESENTATIONS tab of the public website (ffb.jaeb.org)

How to Get Involved