Project Grant R01FD007628

GYRATE ATROPHY OCULAR AND SYSTEMIC STUDY (GYROS) - 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