Study of RS1 Ocular Gene Transfer for X-linked Retinoschisis

A Phase I/IIa Study of RS1 Ocular Gene Transfer for X-linked Retinoschisis

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.

Study Overview

• Status: Completed
• Conditions: Retinoschisis; X-Linked
• Intervention / Treatment: Biological: RS1 AAV Vector

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.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 to use effective barrier (male or female condom) of contraception starting two weeks before 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 starting two weeks before 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).

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, which could be used to treat any manifest ocular inflammation, would be contraindicated.
• Participant has significant liver disease with elevated liver enzymes (greater than or equal to 2.5 times upper limit of normal [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 visual acuities within five letter differences of one another, the choice of study eye will be determined at the discretion of the Investigator in consultation with the participant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; 1e9 vg/eye	Biological: RS1 AAV Vector; Gene transfer by intravitreal injection of the RS1 AAV vector (AAV8-scRS/IRBPhRS)
Experimental: Cohort 2; 1e10 vg/eye	Biological: RS1 AAV Vector; Gene transfer by intravitreal injection of the RS1 AAV vector (AAV8-scRS/IRBPhRS)
Experimental: Cohort 3; 1e11 vg/eye	Biological: RS1 AAV Vector; Gene transfer by intravitreal injection of the RS1 AAV vector (AAV8-scRS/IRBPhRS)
Experimental: Cohort 4; 1e11 vg/eye	Biological: RS1 AAV Vector; Gene transfer by intravitreal injection of the RS1 AAV vector (AAV8-scRS/IRBPhRS)
Experimental: Cohort 5; 3e11 vg/eye	Biological: RS1 AAV Vector; Gene transfer by intravitreal injection of the RS1 AAV vector (AAV8-scRS/IRBPhRS)
Experimental: Cohort 6; Not to exceed 6e11 vg/eye	Biological: RS1 AAV Vector; Gene transfer by intravitreal injection of the RS1 AAV vector (AAV8-scRS/IRBPhRS)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events (AEs) Affecting Ocular Function That Differ Clinically From Those Expected in the Normal Course of Progression of XLRS	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.	Day 0 through Year 2, inclusive

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Electroretinography Combined Response Amplitudes	Change in electroretinography combined response amplitudes from average of baseline 1 and 2 measurements. The higher the amplitude, the better.	Baseline 1 through Year 2
Mean Change in Best Corrected Visual Acuity	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).	Baseline 1 through Year 2
Median and Distribution of Change in Best-Corrected Visual Acuity	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).	Baseline 1 through Year 2
Formation of Circulating Systemic Anti-AAV or Anti-RS1 Antibodies	Formation of circulating systemic anti-AAV or anti-RS1 antibodies assessed via serologic testing	Day 0 through end of study participation (Year 5 or Year 7)
Change in Retinal Structure as Measured by Optical Coherence Tomography	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.	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	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.	Baseline 1 through end of study participation (Year 5 or Year 7)

Collaborators and Investigators

• Sponsor: VegaVect, Inc.
• Collaborators: National Eye Institute (NEI)
• Investigators: Principal Investigator: Laryssa A Huryn, M.D., National Eye Institute (NEI)

Publications and helpful links

General Publications

• Vijayasarathy C, Zeng Y, Marangoni D, Dong L, Pan ZH, Simpson EM, Fariss RN, Sieving PA. Targeted Expression of Retinoschisin by Retinal Bipolar Cells in XLRS Promotes Resolution of Retinoschisis Cysts Sans RS1 From Photoreceptors. Invest Ophthalmol Vis Sci. 2022 Oct 3;63(11):8. doi: 10.1167/iovs.63.11.8.
• Vijayasarathy C, Sardar Pasha SPB, Sieving PA. Of men and mice: Human X-linked retinoschisis and fidelity in mouse modeling. Prog Retin Eye Res. 2022 Mar;87:100999. doi: 10.1016/j.preteyeres.2021.100999. Epub 2021 Aug 11.
• Mishra A, Vijayasarathy C, Cukras CA, Wiley HE, Sen HN, Zeng Y, Wei LL, Sieving PA. Immune function in X-linked retinoschisis subjects in an AAV8-RS1 phase I/IIa gene therapy trial. Mol Ther. 2021 Jun 2;29(6):2030-2040. doi: 10.1016/j.ymthe.2021.02.013. Epub 2021 Feb 15.
• Cukras C, Wiley HE, Jeffrey BG, Sen HN, Turriff A, Zeng Y, Vijayasarathy C, Marangoni D, Ziccardi L, Kjellstrom S, Park TK, Hiriyanna S, Wright JF, Colosi P, Wu Z, Bush RA, Wei LL, Sieving PA. Retinal AAV8-RS1 Gene Therapy for X-Linked Retinoschisis: Initial Findings from a Phase I/IIa Trial by Intravitreal Delivery. Mol Ther. 2018 Sep 5;26(9):2282-2294. doi: 10.1016/j.ymthe.2018.05.025. Epub 2018 Jul 7.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2015
• Primary Completion (Actual): April 25, 2024
• Study Completion (Actual): October 16, 2024

Study Registration Dates

• First Submitted: December 16, 2014
• First Submitted That Met QC Criteria: December 16, 2014
• First Posted (Estimated): December 17, 2014

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 24, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: X-Linked; AAV Vector; Retinoschisis; Gene Transfer
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Diseases; Retinal Degeneration; Retinoschisis
• Other Study ID Numbers: 15EI0038; 15-EI-0038 (Other Grant/Funding Number: National Eye Institute (NEI))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No