Pompe disease, which belongs to a group of diseases known as glycogen storage disease, is inherited in an autosomal recessive manner and results in a deficiency in the enzyme alpha-glucosidase (GAA). This causes lysosomal dysfunction and the abnormal accumulation of glycogen in the body. 

The severity of its presentation largely depends on the remaining levels of GAA activity. In infantile-onset Pompe disease (IOPD), patients have less than 1% of residual GAA activity and an extremely poor prognosis. In late-onset Pompe disease (LOPD), patients can have up to 20% of GAA activity and experience better clinical outcomes (although the disease still eventually leads to death if left untreated).  

The treatment of Pompe disease has undergone a major step forward with the introduction of enzyme replacement therapy. Enzyme replacement therapy works by introducing recombinant human GAA (rhGAA) into the patient, ameliorating the effects of low GAA activity.

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And what do we know of its impact on clinical outcomes? “[Enzyme replacement therapy] can extend lifespan in IOPD and slow down or stabilize progression in LOPD,” Eggers and colleagues wrote in EMBO Molecular Medicine. 

The Limitations of Enzyme Replacement Therapy 

Despite the overall benefits of enzyme replacement therapy, it has certain weaknesses that limit its efficacy in patients with Pompe disease. 

In IOPD, enzyme replacement therapy has indeed been shown to improve survival; however, a closer look shows that severe disease manifestations eventually arise in long-term users. Studies indicate patients can begin to develop cognitive problems and experience frequent treatment failures. This is probably due to the formation of neutralizing anti-rhGAA in the patient.

In LOPD, enzyme replacement therapy has indeed been shown to stabilize motor and respiratory function; however, researchers have also noted that the response in this subset of patients is highly variable. A high percentage of patients with LOPD continue to rely on locomotor and respiratory support despite being on enzyme replacement therapy. 

“The limited efficacy of [enzyme replacement therapy] with rhGAA has been ascribed to its pharmacokinetics which is characterized by high, short‐lasting peaks of enzyme activity in the bloodstream resulting in limited biodistribution and insufficient and/or transient restoration of enzyme activity in affected tissues (particularly skeletal muscle and central nervous system),” Mingozzi and Colella wrote in Human Gene Therapy. 

In summary, while enzyme replacement therapy provides relief to many patients from the worst symptoms of Pompe disease, it cannot be regarded in any way as an absolute cure.

Stable Enzyme Secretion

There is a clear appetite among medical researchers to pursue gene therapy as a solution for diseases of a genetic origin. The reasons for this are twofold: first, existing treatments in many genetic diseases are not curative and merely prolong survival; second, funding for gene therapy research has increased in recent years, allowing researchers to carry out their work in earnest. 

“Gene therapy holds the promise of an efficacious treatment for metabolic diseases and particularly for [Pompe disease],” Eggers and colleagues wrote. 

In Pompe disease, one approach to gene therapy involves systemically delivering an adeno-associated virus (AAV) vector expressing GAA under the control of a liver-specific promoter. This version of gene therapy allows for liver-directed synthesis and secretion of GAA, providing a stable source of enzyme secretion into the circulatory system. 

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Eggers and colleagues conducted a study on gene therapy using GAA knockout mice. They introduced to the mouse models an AAV8 vector expressing a codon-optimized cDNA of the human GAA under the control of a murine muscle creatine kinase promoter/enhancer combination.  

The researchers discovered the therapy led to a “robust, dose-dependent increase in GAA activity at therapeutic, supraphysiological levels.” The result of this increase in GAA activity was glycogen clearance and functional improvement in the mouse models. 

A Potential Way Forward? 

This and other similar studies support the AAV-based approach in Pompe disease gene therapy. Today, researchers are studying the best approach to gene therapy based on target tissues, such as the liver, muscles, and the central nervous system. 

“Given the different manifestations of Pompe disease, which essentially make IOPD a different disease from LOPD, it is unlikely that one gene therapy will address all of the [Pompe disease] manifestations,” Colella and Mingozzi wrote. 

This means that any viable, long-term gene therapy solution to Pompe disease must first pass through rigorous research to ensure it is best suited to the subtype of Pompe disease it is attempting to treat. Clinical studies designed with extended, long-term follow-up of participants are ideal for researchers to fully appreciate the implications of gene therapy. 

In addition, the clinical endpoints for research involving gene therapy need to be defined carefully. This is not easily accomplished, given that Pompe disease is a progressive, chronic disease. We understand that muscle and respiratory function are key endpoints in any therapy for Pompe disease, but at what stage do we consider the therapy to be a success? For example, in terms of muscle function, do we aim for complete muscle recovery, or are we satisfied with partial recovery with no further deterioration?

As researchers grapple with these matters, we have much reason to believe that gene therapy can very well represent the next evolution in the therapeutic landscape of Pompe disease, potentially paving the way for even more advanced treatments in the years to come. 


Eggers M, Vannoy CH, Huang J, et al. Muscle-directed gene therapy corrects Pompe disease and uncovers species-specific GAA immunogenicityEMBO Mol Med. 2022;14(1):e13968. doi:10.15252/emmm.202113968

Colella P, Mingozzi F. Gene therapy for Pompe disease: the time is nowHum Gene Ther. 2019;30(10):1245-1262. doi:10.1089/hum.2019.109