Interferon Gamma-1b Administered Topically for Macular Edema/Intraretinal Schisis Cysts in Rod-Cone Dystrophy (RCD) and Enhanced S-Cone Syndrome (ESCS)

Background:

- People with rod-cone dystrophy (RCD) or enhanced S-cone syndrome (ESCS) have excess fluid under the retina of their eye. This can cause vision loss. The medicine interferon gamma-1b may help people with these diseases.

Objectives:

- To see if interferon gamma-1b eyedrops are safe for people with RCD or ESCS. To see if the medicine can decrease retina fluid and help prevent vision loss.

Eligibility:

- People at least 12 years old with RCD or ESCS. Those with ESCS must have two mutations in the NR2E3 gene.

Design:

* Participants will be screened with medical history, physical exam, eye exam, and blood tests.
* Participants will stay at NIH for 3 days and get the first eyedrops.
* Participants will give themselves 4 study eyedrops 4 times daily for 2 weeks and keep a diary.
* Participants will have 5 outpatient visits over 8 weeks, 2 of which are telephone assessments. They may have:
* Repeats of screening tests.
* Questionnaires.
* Small piece of skin removed.
* Eye exams, including eye dilation and tasks on computer screens.
* Fluorescein angiography. A dye injected into an arm vein will travel to the blood vessels in the eyes. A camera will take pictures.
* Electroretinography. Participants will sit in the dark wearing eyepatches. A small electrode will be taped to the forehead. After 30 minutes, researchers will remove the eyepatches and put in numbing eyedrops and contact lenses. Participants will watch flashing lights.
* Electrooculography. Electrodes will be attached outside of the eyes and eye function will be measured in the dark and the light.
* Participants will have a follow-up visit after 52 weeks.

Objective:

Rod-cone dystrophy (RCD) is a term applied to a number of genetically heterogenous diseases presenting with night vision abnormalities, visual field defects and reduced rod electroretinography responses. Enhanced S-Cone syndrome (ESCS) is a rare autosomal recessive retinal disease with a developmental and a degenerative aspect. Macular cystic changes, often florid and usually resulting in a reduction of central acuity, are frequently associated with both diseases. The reason for this association is not well understood. Acetazolamide (Diamox) and Dorzolamide (Trusopt) have been reported to have variable success in reducing these cystic changes but the effect is frequently inadequate. The objective of this study is to evaluate the safety and potential efficacy of Interferon (IFN) gamma-1b administered topically for macular edema/retinal schisis cysts in RCD and ESCS. Possible disease-related pathophysiologic mechanisms will be explored using induced pluripotent stem cell (iPSC) protocols leading to iPSC-derived retinal pigment epithelium (RPE) and photoreceptor generation.

Study Population:

Up to five participants with RCD with significant macular cystic changes and up to five participants with ESCS with significant macular cystic changes will be enrolled to receive IFN gamma-1b administered topically in one eye. However, up to an additional two participants may be enrolled in order to obtain the five participants in each disease group to be included in the primary analysis if any participants withdraw from the study prior to receiving five days of treatment.

Design:

This is a single-center, prospective, uncontrolled, unmasked pilot Phase I/II study of the safety, tolerability and possible efficacy of IFN gamma-1b in participants with RCD and ESCS and macular cystic changes. One eye of up to five participants with RCD with significant macular cystic changes and up to five participants with ESCS with significant macular cystic changes \[evidenced by optical coherence tomography (OCT) \>275 microns central macular thickness and/or disruption of foveal contour\] will receive topical IFN gamma-1b instilled as drops on the cornea. The initial stage of the study will include two participants from each disease category. Once all four participants have completed the 8-week visit, enrollment will be halted. Safety Adverse Event Review Committee members unaffiliated with the study will review the data as a preliminary assessment of safety and efficacy and to determine whether enrollment should continue. If the committee determines enrollment will continue, three additional participants with RCD and three participants with ESCS will be enrolled. The study will be completed once the final participant has received one year of follow-up.

Outcome Measures:

The primary outcome measure related to the safety and tolerability of IFN gamma-1b administered topically at the prescribed dosage for macular cystic changes in participants with RCD and ESCS will be assessed by the number and severity of adverse events related to the IP and the number of withdrawals at 52 weeks (one year) post-administration. Additional safety of IFN gamma-1b administered topically in participants with RCD and ESCS will be determined from the assessment of retinal function, ocular structure and occurrence of adverse events at all time points. Secondary outcomes include changes in visual function including visual acuity and microperimetry, and retinal imaging with OCT and fluorescein angiography.

Eligibility Criteria:
* INCLUSION CRITERIA:

To be eligible, the following inclusion criteria must be met, where applicable.

1. Participant must be 12 years of age or older.
2. Participant (or legal guardian or legal representative) must understand and sign the protocol informed consent.
3. Participant is willing to comply with the study procedures and is expected to be able to return for all study visits.
4. Participant must carry a clinical diagnosis of RCD or ESCS.
5. ESCS participant must have molecular confirmation with two alleles for NR2E3 gene mutations
6. Female participant of childbearing potential must not be pregnant or breast-feeding, must have a negative pregnancy test at screening and must be willing to undergo pregnancy tests at scheduled study visits.
7. Female participant of childbearing potential, and any male participant able to father children must have (or have a partner who has) had a hysterectomy or vasectomy, be completely abstinent from intercourse or must agree to practice two reliable methods of contraception while taking the IP and six weeks after completion. Acceptable methods of contraception include:

   * Hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or vaginal ring);
   * Intrauterine device;
   * Barrier methods (diaphragm, condom) with spermicide; or
   * Surgical sterilization (tubal ligation).

EXCLUSION CRITERIA:

A participant is not eligible if any of the following exclusion criteria are present.

1. Participant has a history of other ocular disease likely to contribute significantly to visual disruption (e.g., optic neuropathy, glaucoma, uveitis, or other retinal disease).
2. Participant has had diagnosis or treatment of a malignancy (excluding non-melanoma skin cancer) within the previous five years.
3. Participant has received investigational treatment in another clinical study related to an ocular condition in the last six months.
4. Participant is pregnant, lactating, planning to become pregnant (or father a child) during the study follow-up period.
5. Participant is allergic to fluorescein dye.
6. Participant has a systemic condition that, in the opinion of the investigator, would preclude participation in the study (e.g., multiple sclerosis (MS), as IFN gamma may cause MS exacerbations).

Study Eye Eligibility Criteria

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

Study Eye Inclusion Criteria

1. The study eye must retain adequate fixation to allow for completion of protocol assessments.
2. The study eye must have macular cystic changes (\>275 microns and/or disruption of foveal contour on OCT).

Study Eye Exclusion Criteria

1. The study eye has lens, cornea, or other media opacities that preclude adequate visualization and testing of the retina.
2. The study eye has undergone intraocular surgery within 6 months prior to enrollment.
3. The study eye has a disease that may confound the outcome of the study \[e.g., choroidal neovascularization (CNV) in the fovea or parafoveal area\].
4. Participant is unwilling to discontinue wearing a contact lens in the study eye during IP administration.

Study Eye Selection Criteria in Cases of Bilateral Disease

RCD and ESCS usually affect both eyes to a similar degree. In case both eyes of a participant meet the study eye eligibility criteria, the following criteria will be used to select the study eye:

* The eye with more intraretinal fluid will be selected as the study eye;
* If both eyes have similar levels of intraretinal fluid, the eye with worse visual acuity will be selected as the study eye;
* If both eyes have the similar levels of intraretinal fluid and visual acuities, the right eye will be selected as the study eye.