Natural History of Photoreceptor Degeneration in USH1B: Clinical Parameters and Validation of Functional Vision Tests in MYO7A

Natural History of Photoreceptor Degeneration Related to USH1B: Clinical Parameters and Validation of Functional Vision Tests in MYO7A

Inherited retinal diseases (IRDs) are a group of degenerative disorders that cause progressive vision loss. Retinitis pigmentosa (RP) is the most common form, with a global prevalence of approximately 1 in 4,500. About 20-30% of these cases are syndromic, most notably Usher syndrome (USH), which combines hearing loss with visual impairment. Usher syndrome type 1 (USH1), the most severe form, presents at birth with profound sensorineural hearing loss, vestibular areflexia, and early-onset retinal degeneration. Biallelic mutations in the MYO7A gene, which define the USH1B subtype, account for 70% of USH1 cases. There is currently no treatment available for this serious condition. The objective of the study is to characterize the natural history of retinal degeneration in USH1B patients and to validate functional vision tests using virtual reality and patient-reported outcome questionnaires.

Inherited retinal diseases (IRDs) are a heterogeneous group of disorders that gradually lead to severe visual impairment, with limited therapeutic options available. Rod dystrophy, also known as retinitis pigmentosa (RP), is the most common form of IRD, with an estimated global prevalence of 1 in 4,500. Approximately 20% to 30% of rod-cone dystrophy cases are syndromic, with Usher syndrome (USH) being the most frequent. USH has an estimated prevalence of 1 to 4 per 25,000 individuals and accounts for 50% of all cases of deafblindness and 3% to 6% of all cases of childhood deafness.

Usher syndrome type 1 (USH1) is the most severe form of the disease. It typically presents with congenital severe-to-profound sensorineural hearing loss, vestibular areflexia, and early-onset rod-cone dystrophy, usually within the first decade of life. Mutations in nine different genes have been associated with USH1, among which biallelic mutations in the MYO7A gene account for approximately 70% of cases. This specific subtype is referred to as USH1B.

There is currently no approved treatment for USH1B, representing a significant unmet medical need for this severe condition.

Objectives:

1. To study the natural history of retinal degeneration in a large USH1B patient cohort.
2. To validate functional vision tests based on virtual reality, along with two patient-reported outcome questionnaires.

Inclusion Criteria:

• Be at least 3 years old;
• Have a clinical diagnosis of USH1 in both eyes, meaning subjects with congenital profound deafness, vestibular dysfunction, and rod dystrophy, carrying biallelic class 4 or 5 variants in the MYO7A gene;
• Be affiliated with or beneficiary of a social security system (according to article L1121-8-1 of the French Public Health Code);

For participants in the MOST-VR mobility test and VR-ViSA visual search test (Streetlab), additional criteria apply:

• Sufficient knowledge of spoken and signed French to ensure understanding of tasks and instructions;
• Have a cochlear implant allowing comprehension of auditory instructions for the virtual reality mobility test and a MMSE score ≥ 20/25;
• Age between 18 and 75 years.

Exclusion Criteria:

• Unable to participate in all study visits;
• Expected to enter an experimental treatment trial at any time during this study;
• Presence of ocular conditions that may affect eye status other than retinitis pigmentosa (e.g., history of retinal detachment, glaucoma, vein occlusion, diabetic retinopathy, etc.);
• Participation in the previous gene replacement trial (USHSTAT, NCT01505062);
• Pregnant, delivering, or breastfeeding women (according to article L1121-5 of the French Public Health Code);
• Persons deprived of liberty by judicial or administrative decision (article L1121-6 of the French Public Health Code);
• Adults under legal protection measures or unable to provide consent (article L1121-8 of the French Public Health Code).

For participants in the MOST-VR mobility and VR-ViSA visual search tests, the following non-inclusion criteria apply:

• MMSE score without visual items ≤ 20/25;
• Physical or cognitive impairment that could interfere with mobility;
• Medication that may cause motor, visual, or cognitive disorders (e.g., APS, neuroleptics) or interfere with study assessments.