ATSN-201 Gene Therapy in RS1-Associated X-linked Retinoschisis

A Phase 1/2/3, Open-Label, Dose Escalation, Dose Expansion and Randomized, Controlled Study to Evaluate the Safety and Efficacy of ATSN-201 Gene Therapy in Subjects With RS1-Associated X-linked Retinoschisis (LIGHTHOUSE)

This study will evaluate the safety and efficacy of ATSN-201 in subjects ≥ 6 years of age with RS1-associated X-linked retinoschisis (XLRS).

The study is designed in three parts: a dose escalation phase (Part A), a dose expansion phase (Part B) and a randomized, controlled phase (Part C).

In Part C of the study, eligible patients who enroll in this study will be randomly assigned to be treated with ATSN-201 or to have no treatment; subjects assigned to ATSN-201 will receive the drug as a one-time subretinal injection of ATSN-201 in one eye or both eyes, depending on whether only one or both eyes meet criteria for treatment. Subjects will have regular assessments for 1 year as part of the Main Study Period and additional assessments over the next 4 years as part of the Extension Study Period.

Subjects who do not receive treatment as part of the control group can choose to receive ATSN-201 in one or both eyes after the 1-year Main Study Period if eligible.

Part A and B:

Inclusion Criteria:

1. Age ≥ 18 for Cohorts 1 through 4, and age ≥ 6 years and < 18 years for Cohort 5.
2. Male patients with clinical diagnosis of XLRS caused by mutations in RS1.
3. Best corrected visual acuity (BCVA) in study eye of 34 to 73 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (corresponding to a Snellen acuity of 20/200 to 20/40).
4. Presence of foveal schisis and /or parafoveal/perifoveal schisis in the study eye on SD-OCT per the Principal Investigator.

Exclusion Criteria:

1. Pre-existing eye conditions in the study eye that would contribute significantly to an increased risk of visual loss from a subretinal injection (eg, advanced glaucoma, optic neuropathy, uveitis, corneal transplants).
2. Any intraocular surgery (including laser treatment) in the study eye within 6 months prior to Screening or any intraocular surgery anticipated in the study eye during the first 12 months of the study.
3. Treatment in a prior ocular gene or cell therapy study.

Part C:

Inclusion Criteria:

Note: For patients ineligible for bilateral dosing based on the ocular exclusion criteria, the same eye must meet all ocular inclusion criteria, but none of the ocular exclusion criteria, to be eligible for unilateral dosing.

General All of the following criteria must be met for unilateral or bilateral dosing.

1. Age ≥ 6 years.

2. Genetically male patients with clinical diagnosis of XLRS caused by pathogenic or likely pathogenic mutations in RS1 OR Genetically female patients with clinical diagnosis of XLRS caused by biallelic pathogenic or likely pathogenic mutations in RS1.

   Ocular At least 1 eye must meet all of the following criteria for both unilateral and bilateral dosing.

3. BCVA of 34 to 73 ETDRS letters (corresponding to a Snellen acuity of 20/200 to 20/40).

4. Presence of foveal schisis on SD-OCT.

Exclusion Criteria:

General None of the following criteria can be met for unilateral or bilateral dosing.

1. Treatment with any carbonic anhydrase inhibitor (oral or topical) within 1 month prior to Screening.
2. Treatment in a prior ocular gene or cell therapy study.
3. Absence of macular schisis.
4. BCVA better than 75 ETDRS letters (corresponding to a Snellen acuity of 20/32).
5. Pre-existing eye conditions that would contribute significantly to an increased risk of visual loss from a subretinal injection (eg, advanced glaucoma, optic neuropathy, uveitis, corneal transplants).
6. Any intraocular surgery (including laser treatment) within 6 months prior to Screening or any intraocular surgery anticipated during the first 12 months of the study.