¹³C/³¹P MRS Metabolic Biomarkers of Disease Progression and Response to AAV Delivery of hGAA in a Mouse Model of Pompe Disease

The development of therapeutic clinical trials for glycogen storage disorders, including Pompe disease, has called for non-invasive and objective biomarkers. Glycogen accumulation can be measured in vivo with ¹³C MRS. However, clinical implementation remains challenging due to low signal-to-noise. On the other hand, the buildup of glycolytic intermediates may be detected with ³¹P MRS. We sought to identify new biomarkers of disease progression in muscle using ¹³C/³¹P MRS and ¹H HR-MAS in a mouse model of Pompe disease (Gaa^-/-). We evaluated the sensitivity of these MR biomarkers in vivo after treatment using an adeno-associated virus vector 2/9 encoding hGAA driven by the desmin promotor. ³¹P MRS showed significantly elevated phosphomonoesters (PMEs) in Gaa^-/- compared to control at 2 (0.06 ± 0.02 versus 0.03 ± 0.01; p = 0.003), 6, 12, and 18 months of age. Correlative ¹H HR-MAS measures in intact gastrocnemius muscles revealed high glucose-6-phosphate (G-6-P). After intramuscular AAV injections, glycogen, PME, and G-6-P were decreased within normal range. The changes in PME levels likely partly resulted from changes in G-6-P, one of the overlapping phosphomonoesters in the ³¹P MR spectra in vivo. Because ³¹P MRS is inherently more sensitive than ¹³C MRS, PME levels have greater potential as a clinical biomarker and should be considered as a complementary approach for future studies in Pompe patients.