Study of RS1 Ocular Gene Transfer for X-linked Retinoschisis

NCT02317887 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 15EI003815-EI-0038
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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.

Conditions

Retinoschisis; X-Linked

Keywords

Gene Transfer; X-Linked; Retinoschisis; AAV Vector

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Change in Electroretinography Combined Response Amplitudes

  Baseline 1 through Year 2

• Mean Change in Best Corrected Visual Acuity

  Baseline 1 through Year 2

• Median and Distribution of Change in Best-Corrected Visual Acuity

  Baseline 1 through Year 2

• Formation of Circulating Systemic Anti-AAV or Anti-RS1 Antibodies

  Day 0 through end of study participation (Year 5 or Year 7)

• Change in Retinal Structure as Measured by Optical Coherence Tomography

  Baseline 1 through end of study participation (Year 5 or Year 7)

Study Arms (6)

Cohort 1

EXPERIMENTAL

1e9 vg/eye

Biological: RS1 AAV Vector

Cohort 2

EXPERIMENTAL

1e10 vg/eye

Biological: RS1 AAV Vector

Cohort 3

EXPERIMENTAL

1e11 vg/eye

Biological: RS1 AAV Vector

Cohort 4

EXPERIMENTAL

1e11 vg/eye

Biological: RS1 AAV Vector

Cohort 5

EXPERIMENTAL

3e11 vg/eye

Biological: RS1 AAV Vector

Cohort 6

EXPERIMENTAL

Not to exceed 6e11 vg/eye

Biological: RS1 AAV Vector

Interventions

RS1 AAV Vector BIOLOGICAL

Gene transfer by intravitreal injection of the RS1 AAV vector (AAV8-scRS/IRBPhRS)

Cohort 1; Cohort 2; Cohort 3; Cohort 4; Cohort 5; Cohort 6

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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 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 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).

Sponsors & Collaborators

• VegaVect, Inc.: lead
• National Eye Institute (NEI): collaborator

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• 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.

  PMID: 36227606 DERIVED

• 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.

  PMID: 34390869 DERIVED

• 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.

  PMID: 33601057 DERIVED

• 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.

  PMID: 30196853 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Retinoschisis

Condition Hierarchy (Ancestors)

Retinal Degeneration; Retinal Diseases; Eye Diseases

Results Point of Contact

• Title: Dr. Rob Lin
• Organization: VegaVect, Inc.

r.lin@avistatx.com

412-560-9760

Study Officials

• Laryssa A Huryn, M.D.

  National Eye Institute (NEI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 16, 2014
• First Posted: December 17, 2014
• Study Start: February 11, 2015
• Primary Completion: April 25, 2024
• Study Completion: October 16, 2024
• Last Updated: February 14, 2025
• Results First Posted: February 14, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)