Enzyme Replacement Therapy in Glycogen Storage Disorders

Glycogen storage disorders encompass a range of inherited conditions characterised by defective synthesis or degradation of glycogen, with Pompe disease (glycogen storage disease type II) being the prototype treated by enzyme replacement therapy (ERT). ERT delivers recombinant acid α-glucosidase intravenously to supplement the deficient lysosomal enzyme, aiming to clear accumulated glycogen in cardiac and skeletal muscle and to restore organ function. Since its first clinical application, ERT has transformed the natural history of infantile and late-onset forms by reversing cardiomyopathy, stabilising respiratory function and improving muscle strength. Nevertheless, limitations remain: variable skeletal muscle uptake, immune-mediated neutralisation of the therapeutic enzyme, suboptimal targeting of central nervous system involvement and long-term loss of efficacy in some patients. The global significance of ERT extends beyond Pompe disease, having informed therapeutic strategies in other lysosomal storage disorders and spurred development of next-generation approaches, including gene therapy, pharmacological chaperones and improved enzyme formulations. Practical applications now encompass newborn screening, immune tolerance protocols and personalised dosing regimens. Ongoing research continues to refine patient selection, optimise delivery and integrate novel imaging and biomarker tools to monitor treatment response and to guide combination therapies aimed at overcoming residual pathology and preserving quality of life.

Research from Nature Portfolio

Recent advances in non-invasive imaging have enhanced understanding of residual disease under ERT. A study employing multispectral optoacoustic tomography (MSOT) demonstrated high-resolution visualisation of glycogen, water, collagen and lipid signals in the biceps of late-onset Pompe patients, revealing subcellular pathology not detectable by conventional MRI or ultrasound. This approach correlated quantitative optoacoustic metrics with functional measures such as spirometry and muscle testing, offering a sensitive biomarker for therapy monitoring. By validating findings across independent clinical sites, this translational work paves the way for integration of MSOT into complex care pathways and for the early detection of treatment-resistant tissue changes, thereby supporting dose adjustment and combination interventions.

Enzyme Replacement Therapy in Glycogen Storage Disorders publication trend

The graph below shows the total number of articles in enzyme replacement therapy in glycogen storage disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Enzyme Replacement Therapy (ERT): Intravenous delivery of recombinant enzymes to compensate for inherited enzyme deficiencies within lysosomes.

Glycogen Storage Disorders (GSDs): A group of genetic diseases characterised by impaired glycogen synthesis or breakdown, leading to tissue accumulation of glycogen.

Lysosome: A cellular organelle responsible for degradation of macromolecules, including glycogen, via acid hydrolases.

Acid α-Glucosidase (GAA): The lysosomal enzyme deficient in Pompe disease, responsible for hydrolysis of lysosomal glycogen.

Cross-Reactive Immunologic Material (CRIM): The presence (CRIM-positive) or absence (CRIM-negative) of endogenous enzyme protein that influences immune response to infused recombinant enzyme.

Multispectral Optoacoustic Tomography (MSOT): A non-invasive imaging technique combining laser excitation and ultrasound detection to visualise specific molecular components within tissues.

References

1. Non-invasive optoacoustic imaging of glycogen-storage and muscle degeneration in late-onset Pompe disease. Nature Communications (2024).
2. Long term clinical history of an Italian cohort of infantile onset Pompe disease treated with enzyme replacement therapy. Orphanet Journal of Rare Diseases (2018).
3. Effects of a higher dose of alglucosidase alfa on ventilator‐free survival and motor outcome in classic infantile Pompe disease: an open‐label single‐center study. Journal of Inherited Metabolic Disease (2016).
4. Pompe Disease: New Developments in an Old Lysosomal Storage Disorder. Biomolecules (2020).