Objective:

To evaluate the use of the glycogen nuclear Overhauser effect (glycoNOE) magnetic resonance imaging (MRI) for non-invasive glycogen quantification in Pompe disease (PD).

Background:

PD is a rare, inherited, metabolic, multisystemic disorder caused by a functional deficiency of the lysosomal enzyme responsible for breaking down glycogen into glucose, acid α-glucosidase (GAA). Glycogen accumulation in tissues, particularly heart, skeletal and smooth muscle, leads to progressive cardiac, motor, and respiratory dysfunction. Enzyme replacement therapy (ERT) with recombinant human GAA aims to slow disease progression, and is the only approved treatment modality for PD. Current methods for tracking ERT effects in clearing skeletal muscle glycogen require muscle biopsies. Multiple non-invasive methods have been tested to estimate glycogen levels in vivo, including proton magnetic resonance spectroscopy and ultrasound; however, these methods suffer from low detection sensitivity. Recently, it was demonstrated that glycogen levels can be assessed non-invasively with enhanced sensitivity by utilizing the magnetic coupling between aliphatic protons of glycogen and water protons through the relayed nuclear Overhauser effect.

Design/Methods:

Previous glycoNOE experiments in a mouse model of glycogen storage disease type III demonstrated the quantification and high-resolution mapping of glycogen levels in these mice. A separate preliminary study tested glycoNOE in human muscles. Here, we evaluate the use of glycoNOE to quantify skeletal muscle glycogen in a mouse model of Pompe disease by testing GAA knockout mice, ERT-treated GAA knockout mice, and wild-type controls, to assess the correlation between biochemical glycogen level and glycoNOE signal.

Results:

GlycoNOE MRI glycogen quantification could discriminate between controls, GAA knockout and ERT-treated GAA knockout mice.

Conclusions:

This study shows that glycoNOE imaging can detect the ability of ERT treatment to clear glycogen in different muscle groups in GAA knockout mice and serves as a proof of concept for further research. Supported by Amicus Therapeutics, Inc.