Retinal Disease, Retinitis Pigmentosa
Conditions
Keywords
Retinal Disease, subretinal gene therapy, MERTK, retinitis pigmentosa
Brief summary
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).
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.
Interventions
BIOLOGICALSubretinal 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.
Sponsors
King Faisal Specialist Hospital & Research Center
King Khaled Eye Specialist Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Ocular Subretinal administration of rAAV2-VMD2-hMERTK .
Eligibility
Sex/Gender
ALL
Age
14 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Systemic and Ocular Safety | 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
| Measure | Time frame | Description |
|---|---|---|
| Full-field Stimulus Threshold Testing (FST). | 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. |
| Visual Acuity Measurement | 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. |
| Central Foveal Thickness (CFT) on Optical Coherence Tomography (OCT). | 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). | 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. |
Countries
Saudi Arabia
Participant flow
Recruitment details
Six eyes of 6 patients were enrolled in this phase of the study. All patients had the typical clinical signs and symptoms of retinitis pigmentosa and tested positive for MERTK mutation. All patients were recruited from the outpatient clinics at King Khaled Eye specialist Hospital (KKESH) starting September 2011.
Participants by arm
| Arm | Count |
|---|---|
| Recombinant Adeno-Associated Virus Recombinant Adeno-Associated Virus: Ocular Subretinal Injection of a Recombinant Adeno-Associated Virus | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | Recombinant Adeno-Associated Virus |
|---|---|
| Age, Categorical <=18 years | 1 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Age, Continuous | 33.3 years |
| Region of Enrollment Bahrain | 1 participants |
| Region of Enrollment Saudi Arabia | 5 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 6 |
| other Total, other adverse events | 3 / 6 |
| serious Total, serious adverse events | 0 / 6 |
Outcome results
Primary
Systemic and Ocular Safety
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 .
Time frame: 2 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Recombinant Adeno-Associated Virus Injected Eyes | Systemic and Ocular Safety | Corneal abnormalities | 1 Participants |
| Recombinant Adeno-Associated Virus Injected Eyes | Systemic and Ocular Safety | Intraocular pressure changes | 0 Participants |
| Recombinant Adeno-Associated Virus Injected Eyes | Systemic and Ocular Safety | Intraocular inflammation | 0 Participants |
| Recombinant Adeno-Associated Virus Injected Eyes | Systemic and Ocular Safety | Retinal changes | 2 Participants |
| Recombinant Adeno-Associated Virus Injected Eyes | Systemic and Ocular Safety | Afferent pupillary defect | 0 Participants |
| Recombinant Adeno-Associated Virus Injected Eyes | Systemic and Ocular Safety | Macular thinning on OCT | 0 Participants |
| Recombinant Adeno-Associated Virus Injected Eyes | Systemic and Ocular Safety | Cataract | 1 Participants |
| Recombinant Adeno-Associated Virus Injected Eyes | Systemic and Ocular Safety | Toxicity seen on FST | 0 Participants |
| Recombinant Adeno-Associated Virus Injected Eyes | Systemic and Ocular Safety | Systemic events | 0 Participants |
| Fellow Eyes | Systemic and Ocular Safety | Toxicity seen on FST | 0 Participants |
| Fellow Eyes | Systemic and Ocular Safety | Systemic events | 0 Participants |
| Fellow Eyes | Systemic and Ocular Safety | Corneal abnormalities | 0 Participants |
| Fellow Eyes | Systemic and Ocular Safety | Afferent pupillary defect | 0 Participants |
| Fellow Eyes | Systemic and Ocular Safety | Intraocular inflammation | 0 Participants |
| Fellow Eyes | Systemic and Ocular Safety | Cataract | 0 Participants |
| Fellow Eyes | Systemic and Ocular Safety | Intraocular pressure changes | 0 Participants |
| Fellow Eyes | Systemic and Ocular Safety | Retinal changes | 2 Participants |
| Fellow Eyes | Systemic and Ocular Safety | Macular thinning on OCT | 1 Participants |
Secondary
Central Foveal Thickness (CFT) on Optical Coherence Tomography (OCT).
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.
Time frame: 2 years
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Recombinant Adeno-Associated Virus Injected Eyes | Central Foveal Thickness (CFT) on Optical Coherence Tomography (OCT). | CFT at Baseline | 65.80 microns. |
| Recombinant Adeno-Associated Virus Injected Eyes | Central Foveal Thickness (CFT) on Optical Coherence Tomography (OCT). | CFT at 2 years | 69.20 microns. |
| Fellow Eyes | Central Foveal Thickness (CFT) on Optical Coherence Tomography (OCT). | CFT at Baseline | 74.80 microns. |
| Fellow Eyes | Central Foveal Thickness (CFT) on Optical Coherence Tomography (OCT). | CFT at 2 years | 75.00 microns. |
Secondary
Central Macular Thickness (CMT) on Optical Coherence Tomography (OCT).
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.
Time frame: 2 years
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Recombinant Adeno-Associated Virus Injected Eyes | Central Macular Thickness (CMT) on Optical Coherence Tomography (OCT). | CMT at baseline | 128.00 microns. |
| Recombinant Adeno-Associated Virus Injected Eyes | Central Macular Thickness (CMT) on Optical Coherence Tomography (OCT). | CMT at 2 years | 132.33 microns. |
| Fellow Eyes | Central Macular Thickness (CMT) on Optical Coherence Tomography (OCT). | CMT at baseline | 132.67 microns. |
| Fellow Eyes | Central Macular Thickness (CMT) on Optical Coherence Tomography (OCT). | CMT at 2 years | 123.76 microns. |
Secondary
Full-field Stimulus Threshold Testing (FST).
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.
Time frame: 2 years
Population: Six Patients with the clinical diagnosis of RP with a proven MERTK mutation were included. Patients had to be older than 14 years of age and had the viral vector injected into their worse seeing one eye (except case #4).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Recombinant Adeno-Associated Virus Injected Eyes | Full-field Stimulus Threshold Testing (FST). | FST at baseline | -23.34 dB |
| Recombinant Adeno-Associated Virus Injected Eyes | Full-field Stimulus Threshold Testing (FST). | FST at 10 days | -19.58 dB |
| Recombinant Adeno-Associated Virus Injected Eyes | Full-field Stimulus Threshold Testing (FST). | FST at 30 days | -19.22 dB |
| Recombinant Adeno-Associated Virus Injected Eyes | Full-field Stimulus Threshold Testing (FST). | FST at 90 days | -13.94 dB |
| Recombinant Adeno-Associated Virus Injected Eyes | Full-field Stimulus Threshold Testing (FST). | FST at 180 days | -20.01 dB |
| Recombinant Adeno-Associated Virus Injected Eyes | Full-field Stimulus Threshold Testing (FST). | FST at 365 days | -20.59 dB |
| Recombinant Adeno-Associated Virus Injected Eyes | Full-field Stimulus Threshold Testing (FST). | FST at 1.5 year | -21.09 dB |
| Recombinant Adeno-Associated Virus Injected Eyes | Full-field Stimulus Threshold Testing (FST). | FST at 2 years | -20.38 dB |
| Fellow Eyes | Full-field Stimulus Threshold Testing (FST). | FST at 2 years | -15.92 dB |
| Fellow Eyes | Full-field Stimulus Threshold Testing (FST). | FST at baseline | -24.14 dB |
| Fellow Eyes | Full-field Stimulus Threshold Testing (FST). | FST at 180 days | -22.02 dB |
| Fellow Eyes | Full-field Stimulus Threshold Testing (FST). | FST at 10 days | -20.13 dB |
| Fellow Eyes | Full-field Stimulus Threshold Testing (FST). | FST at 1.5 year | -21.66 dB |
| Fellow Eyes | Full-field Stimulus Threshold Testing (FST). | FST at 30 days | -23.40 dB |
| Fellow Eyes | Full-field Stimulus Threshold Testing (FST). | FST at 365 days | -22.26 dB |
| Fellow Eyes | Full-field Stimulus Threshold Testing (FST). | FST at 90 days | -24.68 dB |
Secondary
Visual Acuity Measurement
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.
Time frame: 2 years and up to 5 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Recombinant Adeno-Associated Virus Injected Eyes | Visual Acuity Measurement | Decreased VA at 2 years | 0 Participants |
| Recombinant Adeno-Associated Virus Injected Eyes | Visual Acuity Measurement | Improved VA at 2 years | 3 Participants |
| Recombinant Adeno-Associated Virus Injected Eyes | Visual Acuity Measurement | Stable VA at 2 years | 3 Participants |
| Recombinant Adeno-Associated Virus Injected Eyes | Visual Acuity Measurement | Improvement of VA after 2years | 0 Participants |
| Fellow Eyes | Visual Acuity Measurement | Improvement of VA after 2years | 0 Participants |
| Fellow Eyes | Visual Acuity Measurement | Stable VA at 2 years | 3 Participants |
| Fellow Eyes | Visual Acuity Measurement | Improved VA at 2 years | 1 Participants |
| Fellow Eyes | Visual Acuity Measurement | Decreased VA at 2 years | 2 Participants |