Trial of Subretinal Injection of (rAAV2-VMD2-hMERTK)


This study was to assess the safety of gene transfer via subretinal administration of rAAV2-VMD2-hMERTK in subjects with MERTK-associated retinitis pigmentosa (RP).

Full Title of Study: “Phase I Trial of Ocular Subretinal Injection of a Recombinant Adeno-Associated Virus (rAAV2-VMD2-hMERTK) Gene Vector to Patients With Retinal Disease Due to MERTK Mutations”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: August 2013

Detailed Description

In this phase I open-label, dose-escalation trial, one eye of each patient (the worse-seeing eye in five subjects) will receive a submacular injection of the subretinal rAAV2-VMD2-hMERTK. Patients will be followed daily for 10 days and then at 30, 60, 90, 180, 270, 365, 540, and 730 days post-injection. Data will be collected on (1) full ophthalmologic examination including best-corrected VA, intraocular pressure, color fundus photographs, macular spectral-domain optical coherence tomography, and full-field stimulus threshold test (FST) in both the study and fellow eyes; (2) systemic safety data including CBC, liver, and kidney function tests, coagulation profiles, urine analysis, AAV antibody titers, peripheral blood PCR and ASR measurement; and (3) listing of ophthalmological or systemic adverse effects.


  • Biological: Subretinal administration of rAAV2-VMD2-hMERTKRecombinant Adeno-Associated Virus
    • The study is an open-label, dose-escalation, phase I clinical trial of subretinal administration of rAAV2-VMD2-hMERTK in patients with retinitis pigmentosa due to MERTK mutation.

Arms, Groups and Cohorts

  • Experimental: Subretinal Injection of rAAV2-VMD2-hMERTKRecombinant Adeno-Associated Virus
    • Single arm of 6 patients undergoing subretinal injection of Gene Therapy using rAAV2-VMD2-hMERTKRecombinant Adeno-Associated Virus. Each patient received the injection in one eye.
  • No Intervention: fellow eye without intervention
    • fellow eye without intervention

Clinical Trial Outcome Measures

Primary Measures

  • Systemic and Ocular Safety
    • Time Frame: 2 years
    • Detailed history & physical exam were obtained at baseline visit and each post-injection protocol visit searching for systemic adverse events. Included were electrocardiogram, chest X-ray, complete blood count & differential, prothrombin time & INR, partial thromboplastin time, serum electrolytes, full serum chemistries including liver and renal function, urinalysis; serum antibody titers to AAV2 capsid components and antigen-specific reactivity (ASR) assays; blood analysis by DNA PCR to detect vector spread. Ophthalmic safety monitored changes from baseline included 1) corneal abnormalities, afferent pupillary defect, intraocular inflammation, cataract & intraocular pressure changes; 2) retinal changes based on fundus photos; 3) Macular SD-OCT changes in Central macular (CMT) and central foveal thickness (CFT) measurements when patient fixation allowed it, and 4) full field stimulus threshold (FST) to detect any retinal toxicity .

Secondary Measures

  • Visual Acuity Measurement
    • Time Frame: 2 years and up to 5 years
    • Although candidates may have very severe loss of function, an attempt was made to measure a best-corrected visual acuity using Early Treatment Diabetic Retinopathy Study (ETDRS) charts, and measurements were recorded as the number of letters read on each line of the chart (Diabetic Retinopathy Study Research Group 1985). If a patient was unable to read at least three letters of the first line correctly, the chart distance was progressively halved from the standard 4 m until either the first line was correctly read or the shortest distance of 0.5 m was reached. Patients who were unable to read any letters on the chart were tested for light perception and if they perceived light they were assigned the acuity score equivalent of <20/6400. Measurements were performed at baseline and each protocol follow up visit. Improvement in patients who could read was defined as a gain in 5 letters, and in those with those LP vision only to start seeing hand motion.
  • Full-field Stimulus Threshold Testing (FST).
    • Time Frame: 2 years
    • Full-field stimulus threshold testing (FST) measures sensitivity of the entire visual field by estimating the lowest luminance of a flash that elicits a visual sensation. The FST measurements were performed at baseline and throughout the protocol visits over two years in the study and fellow eyes, and changes in FST results were analyzed.
  • Central Foveal Thickness (CFT) on Optical Coherence Tomography (OCT).
    • Time Frame: 2 years
    • Central foveal thickness (CFT) measurements were performed at baseline and throughout the protocol visits over two years in the study and fellow eyes (whenever possible), and changes in CFT values were analyzed.
  • Central Macular Thickness (CMT) on Optical Coherence Tomography (OCT).
    • Time Frame: 2 years
    • Central macular thickness (CMT) measurements were performed at baseline and throughout the protocol visits over two years in the study and fellow eyes (whenever possible), and changes in CMT values were analyzed.

Participating in This Clinical Trial

Inclusion Criteria

  • MERTK-associated retinal disease; – VA: 20/100 or less in worse eye – Ability to perform tests of visual and retinal function; – Good general health based on a complete physical examination and hematology and chemistry studies performed at a pre-treatment evaluation; – Ability to comply with research procedures; Exclusion Criteria:

  • Pre-existing eye conditions that would preclude the planned surgery or interfere with the interpretation of study endpoints or surgical complications (for example, glaucoma, corneal or lenticular opacities); – Complicating systemic diseases (such as medical conditions causing immunosuppression) that would preclude the gene transfer, ocular surgery or known sensitivity or allergy to medications planned for use in the peri-operative period; – Use of anti-platelet agents that may alter coagulation within 7 days prior to study agent administration; – Use of immunosuppressive medications; – Pregnancy or breastfeeding; – Individuals (males and females) of childbearing potential who are unwilling to use effective contraception for 1 year following agent administration and barrier contraception for 3 months following agent administration; – Any other condition that would prevent a subject from completing follow-up examinations during the course of the study and that, in the opinion of the investigator, makes the subject unsuitable for the study. – Current, or recent (within the past 30 days, or 10 half lives of the drug) participation, in any other research protocol involving investigational agents or therapies. – Recent (within past 6 months) receipt of an investigational biologic therapeutic agent.Subjects will not be excluded based on their gender, race or ethnicity.

Gender Eligibility: All

Minimum Age: 14 Years

Maximum Age: 70 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Fowzan Alkuraya
  • Collaborator
    • King Khaled Eye Specialist Hospital
  • Provider of Information About this Clinical Study
    • Sponsor-Investigator: Fowzan Alkuraya, Head, Developmental Genetics Unit – King Khaled Eye Specialist Hospital
  • Overall Official(s)
    • Fowzan S Alkuraya, MD, Principal Investigator, King Faisal Specialist Hospital & Research Center

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