Safety and Efficacy of rAAV-hRS1 in Patients With X-linked Retinoschisis (XLRS)

Study Overview
=================
Brief Summary
-----------------
This study will evaluate the safety and efficacy of a recombinant adeno-associated virus vector expressing retinoschisin (rAAV2tYF-CB-hRS1) in patients with X-linked retinoschisis. Up to 27 participants will be enrolled and 3 dose levels will be evaluated in a dose escalation format.

Detailed Description
-----------------
This will be a non-randomized, open label, Phase 1/2 dose escalation study. Up to 27 participants will be enrolled. Each participant will receive the study agent by intravitreal injection in one eye on a single occasion. Enrollment will begin with the lowest dose and will proceed to higher doses only after review of safety data by a Data and Safety Monitoring Committee (DSMC). Participants in the dose escalation phase will be ≥ 18 years of age. After the maximum tolerated dose is identified individuals ≥ 6 years of age will be enrolled. Safety will be measured by the number and proportion of participants experiencing adverse events and immune response to RS1. Efficacy will be measured by evaluation of changes in visual function and schisis cavity size.

Official Title
-----------------
A Multiple-Site, Phase 1/2, Safety and Efficacy Trial of a Recombinant Adeno-associated Virus Vector Expressing Retinoschisin (rAAV2tYF-CB-hRS1) in Patients With X-linked Retinoschisis

Conditions
-----------------
X-linked Retinoschisis

Intervention / Treatment
-----------------
* Biological: rAAV2tYF-CB-hRS1


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria include: Retinal disease consistent with a diagnosis of XLRS and documented mutations in the RS1 gene Male individual at least 18 years of age (dose escalation phase) or at least 6 years of age (maximum tolerated dose phase), Able to perform tests of visual and retinal function, Visual acuity specified for each group Not treated with CAIs currently or within 3 months prior to study enrollment, Have acceptable laboratory parameters. Exclusion Criteria include: Prior receipt of any AAV gene therapy product, Pre-existing eye conditions that would preclude the planned intravitreal injection or interfere with interpretation of study endpoints or complications of vector administration.

Ages Eligible for Study
-----------------
Minimum Age: 6 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Groups 1A and 1B<br>Subjects at least 18 y/o treated with a lower dose of rAAV2tYF-CB-hRS1 study drug. | Biological: rAAV2tYF-CB-hRS1<br>* adeno-associated virus vector expressing retinoschisin<br>|
| Experimental: Groups 2 and 2A<br>Subjects at least 6 y/o treated with a middle dose of rAAV2tYF-CB-hRS1 study drug. | Biological: rAAV2tYF-CB-hRS1<br>* adeno-associated virus vector expressing retinoschisin<br>|
| Experimental: Group 3<br>Subjects at least 18 y/o treated with a higher dose of rAAV2tYF-CB-hRS1 study drug. | Biological: rAAV2tYF-CB-hRS1<br>* adeno-associated virus vector expressing retinoschisin<br>|
| Experimental: Group 4<br>Subjects at least 6 y/o treated with a maximum tolerated dose of rAAV2tYF-CB-hRS1 study drug determined for Groups 1A, 1B, 2 and 3. | Biological: rAAV2tYF-CB-hRS1<br>* adeno-associated virus vector expressing retinoschisin<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Adverse Events | Number of participants with ocular adverse events, assessed by standard ophthalmic examination, including slit lamp biomicroscopy, tonometry, and indirect ophthalmoscopy. | From Day 0 to Month 12 (12 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Best Corrected Visual Acuity (BCVA) | Change in ETDRS (Early Treatment of Diabetic Retinopathy) Letter Score. Minimum value=0; Maximum value=100. Higher scores indicate better visual acuity. Change = 12 Mo value - Baseline value | From Day 0 to Month 12 (12 Months) | 
| Change From Baseline in Schisis Cavity Size on Optical Coherence Tomography (OCT) | Change in cystic cavity volume (mm^3), obtained from spectral domain optical coherence tomography (SD-OCT) of the retina, yielding volumetric measures of schisis cavity size and total cyst cavity. Change = 12 Mo value - Baseline value | From Day 0 to Month 12 (12 months) | 
| Change From Baseline in B-wave Amplitude in Electroretinogram (ERG) Responses | Change in dark-adapted 3.0 B-wave amplitude (μV). Change = 12 Mo value - Baseline value | From Day 0 to Month 12 (12 months) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
AAV, XLRS, maculoschisis, retinal degeneration, RS1, adeno-associated virus, gene therapy