Rate of Progression in USH2A Related Retinal Degeneration

This natural history study of patients with USH2A mutations will accelerate the development
of outcome measures for clinical trials. Sensitive, objective outcome measures of retinal
degeneration will greatly facilitate development of treatments for Usher syndrome patients.
Together these approaches are expected to have an impact on understanding USH2A-related
retinal degeneration, developing experimental treatment protocols, and assessing their
effectiveness.

The goals and expected impact of this natural history study are to:

1. Report the natural history of retinal degeneration in patients with biallelic mutations
in the USH2A gene

2. Identify sensitive structural and functional outcome measures to use for future
multicenter clinical trials in USH2A-related retinal degeneration

3. Identify well-defined subpopulations for future clinical trials of investigative
treatments for USH2A-related retinal degeneration

Study Objectives

The primary objectives of the natural history study are to:

1. Characterize the natural history of retinal degeneration associated with biallelic
pathogenic mutations in the USH2A gene over 4 years, as measured using functional
outcome measures (static perimetry, microperimetry, full-field stimulus threshold (FST),
electroretinography (ERG), and visual acuity)

2. Characterize the natural history of retinal degeneration associated with biallelic
pathogenic mutations in the USH2A gene over 4 years, as measured using structural
outcome measures (spectral-domain optical coherence tomography (SD-OCT) ellipsoid zone
(EZ) area)

3. Investigate structure-function relationships for insights into the mechanisms of retinal
degeneration by relating changes in SD-OCT EZ area to visual field progression in
individuals with biallelic pathogenic mutations in the USH2A gene

4. Assess for possible genotype, phenotype, and environmental risk factors with progression
of the outcome measures at 4 years in individuals with biallelic pathogenic mutations in
the USH2A gene

Some additional secondary objectives of this study include:

1. Characterize baseline cross-sectional retinal degeneration associated with biallelic
pathogenic mutations in the USH2A gene (as measured using the main outcome measures)

2. Investigate comorbidities associated with disease (baseline cross-sectional) and disease
progression (longitudinal natural history study) in individuals with biallelic
pathogenic mutations in the USH2A gene

3. Explore patient reported outcome (PRO) measures associated with disease (baseline
cross-sectional) and disease progression (longitudinal natural history study) in
individuals with biallelic pathogenic mutations in the USH2A gene

4. Evaluate variability and symmetry of left and right eye kinetic perimetry and SD-OCT
outcomes at baseline and at 4 years in individuals with biallelic pathogenic mutations
in the USH2A gene

Inclusion Criteria:

- Willing and able to complete the informed consent process

- Ability to return for all study visits over 48 months if in the natural history study

- Age ≥ 8 years

- At least 2 pathogenic or likely pathogenic mutations in USH2A gene from a clinically
certified lab report

Ocular Inclusion Criteria

Both eyes must meet all of the following:

- Clinical diagnosis of a rod-cone degeneration

- Clear ocular media and adequate pupil dilation to permit good quality photographic
imaging

- Ability to perform kinetic and static perimetry reliably

Exclusion Criteria:

- Mutations in genes that cause autosomal dominant RP, X-linked RP, or presence of
biallelic mutations in autosomal recessive RP/retinal dystrophy genes other than USH2A

- Expected to enter experimental treatment trial at any time during this study

- History of more than 1 year of cumulative treatment, at any time, with an agent
associated with pigmentary retinopathy (including hydroxychloroquine, chloroquine,
thioridazine, and deferoxamine)

Ocular Exclusion Criteria

If either eye has any of the following, the patient is not eligible:

- Current vitreous hemorrhage

- Current or any history of rhegmatogenous retinal detachment

- Current or any history of (e.g., prior to cataract or refractive surgery) spherical
equivalent of the refractive error worse than -8 Diopters of myopia

- History of intraocular surgery (e.g., cataract surgery, vitrectomy, penetrating
keratoplasty, or LASIK) within the last 3 months

- Current or any history of confirmed diagnosis of glaucoma (e.g., based on glaucoma
visual field, nerve changes, or glaucoma filtering surgery)

- Current or any history of retinal vascular occlusion or proliferative diabetic
retinopathy

- Expected to have cataract removal surgery during the study

- History or current evidence of ocular disease that, in the opinion of the
investigator, may confound assessment of visual function

- History of treatment for retinitis pigmentosa that could affect the progression of
retinal degeneration (including participation in a clinical trial within the last year
or a retained drug delivery device)