Background:

- X-linked juvenile retinoschisis (XLRS) is caused by changes in the RS1 gene. These changes cause abnormal function of the eye protein retinoschisin. Without normal retinoschisin, the layers of the retina split and vision is lost. Researchers want to try to introduce a healthy RS1 gene into eye cells, to see if this helps retinal cells make healthy retinoschisin. They will put the gene in a virus. The gene and virus package is known as a gene transfer vector (AAV-RS1 vector).

Objectives:

- To see if the AAV-RS1 vector is safe to use in patients with X-linked retinoschisis.

Eligibility:

- Adults 18 and older with a mutation of the RS1 gene, 20/63 vision or worse in one eye, and XLRS.

Design:

• Participants will be screened with genetic tests to confirm XLRS. They will have a medical history and physical and eye exams.
• At visits 1-2, participants will have some or all of the following:
• Medical history
• Physical exam
• Blood and urine tests
• Tuberculosis skin test
• Eye exam
• Vision tests (for one test an intravenous line will be placed in the arm. A dye will be injected that will travel to the blood vessels in the eye).
• At visit 3, the AAV-RS1 vector will be injected with a needle in the study eye. Participants pupils will be dilated. They will get numbing eye drops.
• Visits 4-13 will occur in the 18 months after gene transfer. Many of the above tests will be repeated. Participants will discuss any side effects.
• Visits 14-17 will occur yearly between years 2 and 5.
• After year 5, participants will be contacted yearly by phone for up to 15 years.

Objective: To evaluate the safety and tolerability of ocular AAV-RS1 vector (AAV8-scRS/IRBPhRS) gene transfer to the retina of participants affected with X-linked juvenile retinoschisis (XLRS).

Study Population: Male participants affected with XLRS will receive ocular gene transfer. A maximum of up to 24 participants may be enrolled.

Design: This is a Phase I/IIa, prospective, dose escalation, single-center study. One eye of each participant will receive the AAV-RS1 gene vector application by intravitreal injection. Participants will be closely monitored in conjunction with DSMC oversight. Participants will be followed for 18 months after which they will continue to be followed for up to 5 years after enrollment, or per FDA requirements, for further safety analysis.

Outcome Measures: The primary outcome is the safety of ocular AAV-RS1 vector as determined from assessment of retinal function, ocular structure and occurrence of adverse events and laboratory tests. Secondary outcomes include changes in visual function, electroretinogram (ERG) responses, visual field measurements, retinal imaging with optical coherence tomography (OCT), and the formation of anti-AAV and anti-RS1 antibodies.

Statistics: No formal sample size calculations are used in this Phase I/IIa dose-escalation study.

INCLUSION CRITERIA:

• Participant is male with a mutation in the RS1 gene identified by genotyping.
• Participant must be 18 years of age or older.
• Participant must be able to understand and sign the informed consent.
• Participant must be medically able to comply with the study treatment, study testing and procedures and follow-up visits.
• Participant has at least one eye that meets the study eye criteria listed below.
• Participant must agree to use effective barrier (male or female condom) of contraception starting two weeks before and continuing one year after gene transfer.
• If the participant's partner is able to become pregnant, a second form of effective contraception will be required starting two weeks before and continuing one year after gene transfer.

Effective methods of contraception for this study include:

• hormonal contraception (birth control pills, injected hormones or vaginal ring),
• intrauterine device,
• barrier methods (condom or diaphragm) combined with spermicide,
• surgical sterilization (hysterectomy or tubal ligation in partner or vasectomy).

EXCLUSION CRITERIA:

• Participant is actively receiving another study medication/investigational product (IP).
• Participant has previously enrolled in another gene therapy trial.
• Participant is currently taking, or has taken in the last three months, a systemic carbonic anhydrase inhibitor prior to enrollment/baseline 1 testing.
• Participant has any condition that significantly increases risk of systemic corticosteroids or systemic steroid-sparing immuno-modulatory agents, such as HIV, syphilis, tuberculosis, hepatitis B, hepatitis C, or diabetes mellitus (DM).
• Participant has an underlying serious illness that impairs regular follow-up during the study.
• Participant has had diagnosis or treatment of a malignancy (excluding non-melanoma skin cancer) within the previous five years.
• Participant has pre-existing ocular tumors (excluding non-suspicious nevi).
• Participant has a known allergy to fluorescein dye or other contraindications to obtaining a fluorescein angiogram.
• Participant is on a medication that prevents safe administration of study related drugs.
• Participant has uncontrolled hypertension. (Hypertension judged to be adequately controlled at baseline medical evaluation is not exclusionary.)
• Participant has compromised renal function such that cyclosporine or Cellcept, which could be used to treat any manifest ocular inflammation, would be contraindicated.
• Participant has significant liver disease with elevated liver enzymes (greater than or equal to 2.5 times upper limit of normal [ULN]).
• Participant has low absolute neutrophil count (ANC<1.3 x 10(3)/micro liters).
• Participant has used any biologic immunosuppressive agents within the last three months (within the last six months for rituximab or cyclophosphamide).

STUDY EYE ELIGIBILITY CRITERIA:

The participant must have at least one eye meeting all inclusion criteria and none of the exclusion criteria listed below.

STUDY EYE INCLUSION CRITERIA:

• The study eye must have a best-corrected E-ETDRS visual acuity letterscore of less than or equal to 63 (i.e., worse than or equal to 20/63). The visual acuity from the first baseline visit (Baseline 1) will be used for eligibility determination in case of a change in visual acuity at the second baseline visit (Baseline 2).
• Electroretinogram in the study eye with a scotopic combined response demonstrating a subnormal b wave, consistent with retinoschisis.

STUDY EYE EXCLUSION CRITERIA:

• The study eye has a history of other ocular disease likely to contribute significantly to visual loss or likely to present special risks (e.g., optic neuropathy, advanced glaucoma, uveitis, large bullous schisis cavities or bullous retinal detachment precluding safe intravitreal injection).
• The study eye has lens, cornea, or other media opacities precluding adequate visualization and testing of the retina.
• The study eye has undergone intraocular surgery within six months prior to enrollment.
• The study eye is receiving topical carbonic anhydrase inhibitor, or has received topical carbonic anhydrase inhibitors in the past three months.

STUDY EYE SELECTION CRITERIA:

If both eyes of a participant meet the study eye eligibility criteria, the choice of study eye will be determined as follows:

• The eye with the worse visual acuity will be selected as the study eye.
• If both eyes have visual acuities within five letter differences of one another, the choice of study eye will be determined at the discretion of the Investigator in consultation with the participant.

No participants were enrolled into Cohort 6.

Day 0 to end of study participation (Year 5 or Year 7)

All enrolled participants are at risk.