Study of RS1 Ocular Gene Transfer for X-linked Retinoschisis

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 15 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 not to receive live (attenuated) vaccines prior to dosing and
for some duration following dosing.

- Participant must agree to use effective barrier (male or female condom) of
contraception before dosing 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 before dosing 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).

- Participant agrees to use appropriate sun protection when on immunomodulatory agents.

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 would be
contraindicated.

- Participant has significant liver disease with elevated liver enzymes (greater than or
equal to 2.5 times 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 the same visual acuity, the choice of study eye will be determined
at the discretion of the investigator in consultation with the participant.