Group designation and treatment protocol.

Noninvasive and objective biomarkers for disease-associated pathology are critical for clinical trials. For Fabry disease, one important pathological change due to the deficiency of the lysosomal enzyme α-galactosidase A (α-GAL) caused is accumulation of globotriaosylceramide (Gb3) in dorsal root ganglion (DRG) neurons, which manifests as the overall DRG hypertrophy. Magnetic resonance imaging (MRI) has been successfully used to noninvasively measure DRG enlargement in Fabry patients, and DRG volumetric MRI can be a potential noninvasive biomarker for Gb3 accumulations in DRG neurons in clinical trials. To evaluate disease progression and treatment response in preclinical proof-of-concept studies, we developed an in vivo MRI method to measure DRG size in the G3Stg/GLA knockout mouse model of Fabry disease. Compared to the wild type mice, the DRG enlargement in the Fabry mice was observed as early as 8 weeks of age, and a single administration of the human α-GAL-encoding adeno-associated virus (AAVGLA) normalized the enlarged DRG to the age-matched wild type mice. The DRG normalization was observed within 4 weeks of gene therapy (12 weeks of age) and was sustained up to 24 weeks of age. Furthermore, behavioral testing and histological/immunohistochemistry analyses of the DRG tissues corroborated the MRI findings. Volumetric DRG MRI has the sensitivity to measure Gb3 pathology-induced DRG volume changes and treatment response in live mice and can be a translational imaging biomarker in clinical trials for Fabry disease.