Study of RS1 Ocular Gene Transfer for X-linked Retinoschisis

Phase 1

Completed

Conditions: X-Linked
Retinoschisis

Interventions: Biological: RS1 AAV Vector

Registration Number: NCT02317887

Lead Sponsor: VegaVect, Inc.

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 12

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 4	RS1 AAV Vector	1e11 vg/eye
Group 6	RS1 AAV Vector	Not to exceed 6e11 vg/eye
Group 2	RS1 AAV Vector	1e10 vg/eye
Group 5	RS1 AAV Vector	Not to exceed 3e11 vg/eye
Group 1	RS1 AAV Vector	1e9 vg/eye
Group 3	RS1 AAV Vector	1e11 vg/eye
Cohort 1	RS1 AAV Vector	1e9 vg/eye
Cohort 2	RS1 AAV Vector	1e10 vg/eye
Cohort 3	RS1 AAV Vector	1e11 vg/eye
Cohort 4	RS1 AAV Vector	1e11 vg/eye
Cohort 5	RS1 AAV Vector	3e11 vg/eye
Cohort 6	RS1 AAV Vector	Not to exceed 6e11 vg/eye

Primary Outcome Measures

Name	Time	Method
Adverse Events (AEs) Affecting Ocular Function That Differ Clinically From Those Expected in the Normal Course of Progression of XLRS	Day 0 through Year 2, inclusive	Includes a) substantial functional change (change \>=10 electronic visual acuity letters in best-corrected visual acuity from average of baseline visits), b) decrease in electroretinogram response amplitude (\>=75% from average of baseline visits), c) severe ocular inflammation beyond inflammation anticipated consequent to an intravitreal injection; d) adverse events deemed clinically-related to the intraocular administration technique, and e) abnormal laboratory findings beyond Grade 1 Common Terminology Criteria for Adverse Events v5.0 and/or clinically significantly different than baseline. a)-d) only includes events occurring in the study eye.

Secondary Outcome Measures

Name	Time	Method
Change in Retinal Structure as Measured by Optical Coherence Tomography	Baseline 1 through end of study participation (Year 5 or Year 7)	Change in retinal structure as measured by optical coherence tomography (OCT) compared to average of baseline 1 and 2. Includes a) quantitative measures of total retinal thickness obtained with the Cirrus OCT using macular cube scans, b) qualitative morphologic changes to macula anatomy investigated using the tracking ability of the Heidelberg Spectralis OCT system and c) length of intact ellipsoid zone on the OCT and any findings of restoration of this reflectivity line.
Change in Electroretinography Combined Response Amplitudes	Baseline 1 through Year 2	Change in electroretinography combined response amplitudes from average of baseline 1 and 2 measurements. The higher the amplitude, the better.
Mean Change in Best Corrected Visual Acuity	Baseline 1 through Year 2	Mean change in best corrected visual acuity (BCVA) at Year 2 compared to average of baseline 1 and 2. BCVA is measured via Electronic Visual Acuity (EVA).
Median and Distribution of Change in Best-Corrected Visual Acuity	Baseline 1 through Year 2	Median and distribution of change in best-corrected visual acuity (BCVA) at Year 2 compared to average of baseline 1 and 2. BCVA is measured via Electronic Visual Acuity (EVA).
Formation of Circulating Systemic Anti-AAV or Anti-RS1 Antibodies	Day 0 through end of study participation (Year 5 or Year 7)	Formation of circulating systemic anti-AAV or anti-RS1 antibodies assessed via serologic testing
Change in Central Visual Field Sensitivity as Measured by Microperimetry (MP-1) Visual Field Testing	Baseline 1 through end of study participation (Year 5 or Year 7)	Change in central visual field sensitivity as measured by microperimetry (MP-1) Visual Field testing compared to average of baseline 1 and 2. Includes mean sensitivities, number of scotomatous points and number of points with a significant change in sensitivity.