1 Project Summary/Abstract for GYROS
2 Gyrate atrophy is a rare inherited chorioretinal degeneration that is associated with
3 hyperornithinemia caused by autosomal recessive mutations in the ornithine aminotransferase
4 (OAT) gene and leads to severe loss of vision. The current standard of care treatment is a
5 highly burdensome arginine-restricted diet (ARD) fraught with management complications. The
6 principal investigators are currently developing a gene augmentation therapy, a potential
7 treatment strategy that may preserve or improve vision while avoiding or reducing the
8 need for ARD. To facilitate a future interventional clinical trial, there is a need to characterize
9 the natural history of OAT-related ocular and systemic disease progression. The study aims are:
10 1. Natural History – Characterize the natural history of ornithine levels and retinal
11 degeneration (RD) associated with disease-causing OAT variants in the presence of
12 standard dietary treatment regimens over 4 years, using metabolic measures of fasting
13 plasma and blood spot amino acids panels, functional and structural measures of RD,
14 and patient-reported outcome measures.
15 2. Metabolic-Structure-Function Relationships – Explore the relationships between
16 structural and functional RD outcome measures and plasma ornithine levels.
17 3. Identify Rapid Progressors – Explore the relationship of possible risk factors
18 (genotype, phenotype, environmental, standard care dietary regimen) with severity and
19 progression of outcome measures.
20 This natural history study will inform the future interventional clinical trial design as follows:
21 ¿ Determine within-patient variability of ornithine levels
22 ¿ Develop quantitative measures of progression of the area of preserved retina and
23 establish its reproducibility, sensitivity to change, and relationship with other measures
24 ¿ Establish rates of progression of functional RD, structural RD, and patient-reported
25 outcome measures, and determine which measures are most sensitive to change
26 ¿ Determine primary time points and duration for a planned future treatment trial
27 ¿ Use variability and inter-eye correlation of outcomes for trial sample size calculations
28 ¿ Identify candidates for the future trial, including eligibility criteria based on risk factors
29 and cut points for severity of disease most likely to benefit from treatment
30 ¿ Establish study procedures and workflows