Chorioretinal Degeneration, Gyrata of Choroid and Retina; Atrophy, Gyrate Atrophy, OAT, Ornithine-δ-aminotransferase
Conditions
Keywords
Gyrate Atrophy, OAT
Brief summary
The Gyrate Atrophy Ocular and Systemic Study characterizes the natural history of ornithine levels and retinal degeneration (RD) associated with disease-causing OAT variants in the presence of standard care dietary treatment regimens over 4 years. The research goal is to understand the impact of OAT mutations on plasma ornithine levels and retinal degeneration. Funding Source- FDA OOPD
Detailed description
Gyrate atrophy is a rare inherited chorioretinal degeneration that is associated with hyperornithinemia, an inborn error of metabolism caused by autosomal recessive mutations in the ornithine aminotransferase (OAT) gene. Gyrate atrophy is characterized by childhood-onset nyctalopia and sharply demarcated areas of chorioretinal atrophy that initially involve the midperipheral fundus. The atrophic areas typically coalesce and enlarge towards the posterior pole in the second and third decades of life, leading to severe visual field constriction and vision loss if left untreated. The current standard care treatment of gyrate atrophy is an arginine restricted diet that is implemented in practice using dietary protein restriction with essential amino acid supplementation. However, dietary treatment is highly burdensome on patients and negatively impacts quality of life such that only about \ 20% of patients are able to comply. Strict adherence to dietary protein restriction (particularly through adolescence), essential amino acid supplementation, and nutritional management of body weight especially during intercurrent illness and pregnancy are among the challenges of treatment. Periods of suboptimal dietary control led to plasma ornithine elevation and progressive chorioretinal degeneration. Investigators are developing gene therapy as a potential one-time treatment that could arrest disease progression while avoiding or reducing the need for dietary treatment. To facilitate a future interventional gene therapy clinical trial, there is a need to evaluate natural history of and the relationship between potential clinical trial outcome measures. The objectives of the OAT gene natural history study are as follows: 1. Natural History 1. Characterize the natural history of retinal degeneration associated with disease-causing OAT variants in the presence of standard care dietary treatment regimens over four (4) years, using functional, structural, and patient-reported outcome measures. 2. Characterize the natural history of ornithine levels associated with disease-causing OAT variants in the presence of standard care dietary treatment regimens over four (4) years. 3. Determine within-patient variability of ornithine levels associated with disease-causing OAT variants in the presence of standard care dietary treatment regimens over four (4) years. 4. Evaluate inter-eye correlation on ocular measures. 2. Metabolic-Structure-Function Relationships 1. Explore relationship of structural outcomes with functional outcomes in individuals with disease-causing OAT variants. 2. Explore relationship of plasma ornithine levels with structural and functional outcomes in individuals with disease-causing OAT variants. 3. Identify Rapid Progressors 1. Explore possible risk factors (genotype, phenotype, environmental, comorbidities, and dietary therapy/supplements) for progression of the functional, structural, and patient-reported outcome measures over four (4) years in individuals with disease-causing OAT variants. 2. Explore possible risk factors (genotype, phenotype, environmental, comorbidities, and dietary therapy/supplements) for ornithine levels over four (4) years in individuals with disease-causing OAT variants. The expected impact of the OAT gene natural history study is to inform a future interventional clinical trial design and implementation, including the following: 1. Determine within-patient variability of ornithine levels. 2. Develop quantitative measures of progression of the area of preserved retina and establish its reproducibility, sensitivity to change, and relationship with other measures. 3. Establish rates of progression of retinal degeneration on all functional, structural, and patient-reported outcome measures, and determine which measures are most sensitive to change. 4. Determine primary time points and duration for a planned future treatment trial. 5. Use variability and inter-eye correlation of outcomes for trial sample size calculations. 6. Identify candidates for the future trial, including eligibility criteria based on risk factors and cut points for severity of disease most likely to benefit from treatment. 7. Establish study procedures and workflows for practical implementation of the same testing procedures in a future trial.
Interventions
None listed
Sponsors
Jaeb Center for Health Research
Conquering Gyrate Atrophy Foundation
Foundation Fighting Blindness
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must meet all the following inclusion criteria at the Screening Visit in order to be eligible to enroll into the genetic screening phase. * Willing to participate in the study and able to communicate consent during the consent process. * Willing and able to complete all study visit assessments at each visit over the forty-eight (48) month study period. Age ≥ 12 years. Must meet one (1) of the Genetic Screening Criteria below: * At least 2 disease-causing variants in the OAT gene which are homozygous or heterozygous in trans, based on a report from a clinically certified lab, or a report from a research lab that has been pre-approved by the study Genetics Committee. * At least 2 disease-causing variants in the OAT gene with unknown phase, based on a report from a clinically certified lab, or a report from a research lab that has been pre-approved by the study Genetics Committee, AND must meet both of the following phenotype criteria: .Classic fundus appearance of gyrate atrophy (based on investigator discretion) AND Elevated ornithine levels \>300 μmol/L (documented on any prior lab report). Note: if a participant has a variant(s) of unknown significance, they will still qualify if they meet the Genetic Screening Criteria above. Ocular Inclusion Criteria Participant must meet the following criteria at the Screening Visit to enroll into the genetic screening phase. Both eyes must have a clinical diagnosis of retinal dystrophy. Both eyes must permit good quality photographic imaging (e.g., but not limited to, clear ocular media, adequate pupil dilation, stable fixation).
Exclusion criteria
* Participants must not meet any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Structural Outcome: Characterize Change using Quantitative Measures of Progression of the Area of Preserved Retina | Baseline and every year until study completion (4 years) | Measured by Wide Field Fundus Autofluorescence (FAF) |
| Structural Outcome: Characterize Change using Quantitative Measures of Progression of the Area of Preserved Retina (Use with FAF for assessments) | Baseline and every year until study completion (4 years) | Measured by wide field color photography |
| Metabolic Outcome: Characterize Change in Plasma Ornithine Level | Baseline and every year until study completion (4 years) | Obtained by fasting plasma amino acids panel and evaluated by a central lab |
| Metabolic Outcome: Characterize Change in Blood Spot Ornithine Level | Baseline and every 4 months until study completion (4 years) | Obtained by fasting blood spot test amino acids panel and evaluated by a central lab |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Structural Outcome: Ellipsoid zone (EZ) area | Baseline and every year until study completion (4 years) | Measured by Spectral Domain Optical Coherence Tomography (SD-OCT) |
| Structural Outcome: Area of Post Subcapsular Cataract | Baseline and every year until study completion (4 years) | Measured by Red Reflex Photography |
| Structural Outcome: Foveal Avascular Zone (FAZ) Area and Macular Vessel Density | Baseline and every year until study completion (4 years) | Measured by OCTA Ancillary Test at Subset of Sites |
| Functional Outcome: Visual Field Sensitivity Measured with Quantitative Topographic Analysis (Hill of Vision) | Screening visit and every year until study completion (4 years) with the exception of baseline. | Measured by Octopus 900 Pro |
| Functional Outcome: Early Treatment of Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score | Screening visit and every year until study completion (4 years) with the exception of baseline. | Measured on the Electronic Visual Acuity (EVA) system or ETDRS charts. |
| Functional Outcome: Low Visual Acuity Test - for participants unable to see ETDRS letters | Screening visit and every year until study completion (4 years) with the exception of baseline. | Measured on the Berkeley Rudimentary Vision Test (BRVT) |
| Functional Outcome: ETDRS Best Corrected Low Luminance Visual Acuity Letter Score | Screening visit and every year until study completion (4 years) with the exception of baseline. | Measured on the Electronic Visual Acuity (EVA) system or ETDRS charts. |
| Functional Outcome: Change in Mean Retinal Sensitivity | Baseline and every year until study completion (4 years) | Measured by Fundus-Guided Microperimetry (MP) |
| Functional Outcome: Change in Full-Field Retinal Sensitivity | Baseline and every year until study completion (4 years) | Measured by full-field stimulus threshold (FST) testing to blue, white, and red stimuli |
| Functional Outcome: Change in Retinal Function | Baseline and every year until study completion (4 years) | Measured by full-field electroretinogram (ERG) amplitudes and timing in response to rod- and cone-specific stimuli. |
| Metabolic Outcome: Proline, lysine, glutamine, glutamate, arginine, and related metabolite: creatine and its precursor guanidinoacetate | Two (2) fasting plasma samples collected on two (2) different days, within ten (10) days of Baseline Visit date and every year until study completion (4 years) | Obtained by fasting plasma amino acids panel and evaluated by a central lab |
| Metabolic Outcome: Level of dietary protein control | Baseline and every year until study completion (4 years) | Obtained from serum albumin sample evaluated by a central lab |
Countries
Brazil, Canada, Finland, France, Germany, Italy, United Kingdom, United States
Contacts
STUDY_CHAIRMandeep S. Singh, MD
John Hopkin's - Wilmer Eye Institute
STUDY_CHAIRDavid Valle, MD
John Hopkin's - Wilmer Eye Institute
Outcome results
None listed