Gyrate Atrophy Ocular and Systemic Study

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

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.