Oxidative stress has been implicated in the pathophysiology of many diseases. It is a subject of intense research, and scientists are confident that it plays a role in conditions such as Alzheimer’s disease, cardiac disease, infertility, and hypertension. 

Some scientists see a link between oxidative stress and age-related pathology. Hybertson et al, in their study on oxidative stress in health and disease, wrote, “For the past 40 years or so, oxidative stress has been increasingly recognized as a contributing factor in aging and in various forms of pathophysiology generally associated with aging.” 

In this article, we will be looking at a study conducted by Tarallo et al that seeks to clarify the link between oxidative stress and the efficacy of Pompe disease treatment. 

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Defining Oxidative Stress

First of all, what is oxidative stress? You might think it has a straightforward definition like most things in medicine, but the phrase is overused—by physicians and proponents of alternative medicine and in wellness circles—and there is no consensus on what it strictly means. 

Helmut Sies of the Institute of Biochemistry and Molecular Biology in Germany wrote, “Useful as the term ‘oxidative stress’ may be in research, there has been an inflationary development in research circles and more so in the medical field and, even more than that, in public usage outside scientific endeavors (I would call it ‘over-stressing’ the term). This led to a dilution of the meaning, to overuse and even misuse.” 

However, Sies relayed 2 definitions of oxidative stress:

  • “A disturbance in the proooxidant-antioxidant balance in favor of the former.” 
  • “An imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control and/or molecular damage.” 

In simple terms, oxidative stress occurs when oxidants are more dominant than antioxidants and damages one’s health. However, dig deeper and you will find things are far more complex.

“From its very nature, it is a challenge to combine the basic chemical notion of oxidation-reduction, including electron transfer, free radicals, oxygen metabolites (such as the superoxide anion radical, hydrogen peroxide, hydroxyl radical, electronically excited states such as singlet molecular oxygen, as well as the nitric oxide radical and peroxynitrite) with a biological concept, that of stress,” Sies wrote. 

A Possible Role in Pompe Disease 

We now turn our attention to the clinical study conducted by Tarallo and colleagues on how the correction of oxidative stress can enhance enzyme replacement therapy (ERT) in Pompe disease. 

ERT is the mainstay of Pompe disease treatment today. Several factors are known to affect its efficacy, including the patient’s immunological status, the stage of disease progression, and the age at which treatment is started. 

Read more about Pompe disease therapies 

Tarallo et al speculated that oxidative stress might also be a factor that influences the efficacy of ERT. The reason? They wrote, “Increased stress is expected to be one of the consequences of autophagy impairment and has been in fact observed in Pompe disease. The existence of a crosstalk between the autophagic pathway and oxidative stress has been clearly documented.” 

They evaluated levels of oxidative stress in Pompe disease in the tissues of a GAA knockout (KO) mouse, which is a murine model of Pompe disease generated by disrupting the GAA gene exon 6. They analyzed tissues most impacted by Pompe disease, such as the heart, skeletal muscles, and the liver. They then compared the levels of oxidative stress found in those tissues with those of wild-type animals. 

“In muscles and heart from the [GAA] KO mouse, we found significantly increased ROS levels and lipid peroxidation, while in liver only lipid peroxidation was significantly increased,“ they wrote. “Western blot analysis of the stress marker p-ERK in gastrocnemius also supported the presence of increased oxidative stress.” 

The researchers then studied the impact of oxidative stress on the correction of acid alpha-glucosidase (GAA) activity by recombinant human GAA (rhGAA). They treated six Pompe disease fibroblast cell lines with an rhGAA preparation called alglucosidase-alfa, currently approved for use in treating Pompe disease.

“We found that ROS levels and lipid peroxidation inversely correlated with correction of GAA activity in rhGAA-treated cells, with less efficient correction in cells showing the highest levels of stress,” they wrote. 

Read more about Pompe disease treatment 

The significance of this study is that it shows that the correction of oxidative stress can improve the performance of ERT in patients with Pompe disease. The researchers wrote, “In conclusion, our work provides proof-of-concept evidence that reducing oxidative stress, one of the secondary abnormalities observed in Pompe disease, is a strategy that may be pursued to enhance the effects of ERT.” 

There is still a lot that we do not understand about oxidative stress, but the findings of this study provide evidence that it is worthy of further investigation as a therapeutic target. Improved efficacy of ERT would mean a better quality of life for patients with Pompe disease and slow down disease progression to buy time for more research into possible new treatment innovations. 


Hybertson BM, Gao B, Bose SK, McCord JM. Oxidative stress in health and disease: the therapeutic potential of Nrf2 activationMol Aspects Med. 2011;32(4-6):234-246. doi:10.1016/j.mam.2011.10.006

Tarallo A, Damiano C, Strollo S, et al. Correction of oxidative stress enhances enzyme replacement therapy in Pompe diseaseEMBO Mol Med. Published online October 4, 2021. doi:10.15252/emmm.202114434

Sies H. Oxidative stress: a concept in redox biology and medicineRedox Biol. 2015;4:180-183. doi:10.1016/j.redox.2015.01.002