Every once in a while, a medical breakthrough occurs that alters the status quo completely. We can look to history for examples of this: the discovery of insulin to treat diabetes; the discovery of antibiotics to treat bacterial infections; and the discovery of factor replacement therapy to treat hemophilia. 

It is no exaggeration to suggest that enzyme replacement therapy belongs in this medical hall of fame; it has quite significantly upended the way we think about illnesses such as Pompe disease and improved prognosis in ways previously thought impossible. 

Enzyme replacement therapy was first used in the early 1990s to treat Gaucher disease, a lysosomal storage disorder. Its success opened the door for its use in other lysosomal storage disorders such as Pompe disease. Pompe disease is an excellent candidate for enzyme replacement therapy because it is characterized by the loss of a single enzyme: acid alpha-glucosidase (GAA). 

Continue Reading

“The introduction of [enzyme replacement therapy] over a decade ago has changed the natural course of the disease, primarily because of its notable effect on cardiac muscle,” Meena and colleagues wrote in Molecular Therapy: Methods & Clinical Development. 

The main drivers of pathology in Pompe disease are twofold: defective autophagy and the triggering of a pathogenic cascade that leads to progressive skeletal muscle damage and atrophy. The balance between protein synthesis and degradation is upset, and 2 major signaling pathways regulated by nutrient-sensing kinases are disrupted, namely AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTORC1). 

Read more about Pompe disease etiology 

Since enzyme replacement therapy became available, scientists have been conducting studies on experimental mice to validate various outcome measures. These include glycogen clearance, GAA activity, and muscle function. In terms of muscle strength, scientists have also used a grip strength meter and other objective motor measurements to validate improvements in Pompe disease. 

Multiple studies have concluded that enzyme replacement therapy has a remarkably high therapeutic efficacy, stemming from its most prominent accomplishment: reversing the primary defect of lysosomal glycogen accumulation. 

In recent years, enzyme replacement therapy has become the mainstay treatment for Pompe disease. Ongoing studies suggest that it improves clinical outcomes and prolongs survival. In this regard, it has accomplished the one rare thing in medicine: converting a lethal condition into a manageable one. 

A Possible Next Step 

Despite the relative success of enzyme replacement therapy, some scientists are quick to point out that it lacks certain fundamental mechanisms that prevent it from being a truly curative form of treatment. 

Studies have indicated that the uptake of enzyme replacement therapy in disease-relevant tissues in patients with Pompe disease is often unsatisfactory. One explanation for this is that recombinant human GAA is relatively unstable in blood pH. In addition, this form of therapy does not cross the blood-brain barrier. Researchers have also noted severe anaphylactic reactions in patients who have been newly prescribed enzyme replacement therapy.  

“Alternative therapeutic strategies against [Pompe disease], independent or complementary to [enzyme replacement therapy], are thus still needed,” Borie-Guichot and colleagues wrote in Molecules. 

Therefore, they proposed an alternative therapeutic strategy against Pompe disease that can be used independently or concurrently with enzyme replacement therapy: pharmacological chaperone therapy. This form of therapy aims to restore enzymatic activity by promoting protein stabilization via ligand binding. 

The word “chaperone” refers to a molecule that can assist a protein in returning to its original conformation. Its ability to stabilize the correct conformation of a misfolded protein opens the door for cellular enzyme activity to increase accordingly. 

Pharmacological chaperones only work with a narrow set of proteins: they are not particularly useful when the protein is absent due to mutations or deletions. As a result, their use is limited to the case of missense mutations. 

“Recent studies showed that chaperones may also be able to increase the stability of the endogenous wild-type enzymes, although [pharmacological chaperone] therapy was initially designed to rescue mutant proteins,” Borie-Guchot et al wrote.

“Moreover, preclinical studies showed that [pharmacological chaperones] also improve enzyme stability, lysosomal trafficking and/or activity in cultured Pompe . . . cells incubated with the exogenous recombinant enzymes.” 

Read more about Pompe disease treatment 

It is worth noting that enzyme replacement therapy is so far the only unique approved treatment for Pompe disease in the United States. Despite its contribution to alleviating suffering and extending survival, limitations remain, as mentioned above. Scientists have naturally sought an alternative, one that has a low molecular weight compound. Pharmacological chaperones fit the bill, although significant hurdles remain before they can be approved for widespread use.

One major sticking point when it comes to pharmacological chaperones is that we still need to discover new pharmacological chaperone small molecules that do not demonstrate any inhibition toward GAA. Some scientists think non-iminosugar pharmacological chaperones could potentially solve this problem. 

If pharmacological chaperones become a reality one day, patients with Pompe disease will be left with 2 potent treatments to choose from or to use concurrently. This bodes well for the future of Pompe disease therapeutics and patients with the disease.


Meena NK, Ralston E, Raben N, Puertollano R. Enzyme replacement therapy can reverse pathogenic cascade in Pompe diseaseMol Ther Methods Clin Dev. 2020;18:199-214. doi:10.1016/j.omtm.2020.05.026

Borie-Guichot M, Tran ML, Génisson Y, Ballereau S, Dehoux C. Pharmacological chaperone therapy for Pompe diseaseMolecules. 2021;26(23):7223. doi:10.3390/molecules26237223