Pompe disease is a multisystem disorder caused by mutations in the GAA gene that codes for the enzyme, acid alpha-glucosidase (GAA),1 which breaks down glycogen into glucose to be used as an energy source for the cells. Defects in the enzyme prevent glycogen breakdown, causing a toxic accumulation of glycogen inside the cells. This results in damage to organs and tissues, particularly the muscle cells, causing muscle weakness, heart problems, and effects on other organs.2

Thus, treatment of Pompe disease requires a multidisciplinary team of specialists including cardiologists, neurologists, pulmonologists, neuromuscular specialists, respiratory therapists, occupational therapists, audiologists, genetic counselors, dieticians, and others.

Enzyme Replacement Therapy

Currently, the only available, specific, and effective treatment for Pompe disease is enzyme replacement therapy (ERT),3 which was first approved in 2006 for use in patients with infantile-onset Pompe disease (IOPD).

In ERT, synthetic recombinant human GAA (rhGAA) is administered intravenously every 2 weeks to replace low levels of GAA in affected individuals. The genetically engineered rhGAA binds to mannose-6-phosphate receptors (M6P) on the cell surface and is then taken up by the cell, finally reaching the lysosomes where the active form of the enzyme breaks down glycogen into glucose.

The recommended dose of rhGAA is 20 mg/kg every 2 weeks per the preparation and infusion indications of the manufacturing company, but higher doses of up to 40 mg/kg can also be administered in patients with IOPD.

ERT may lead to adverse events, including mild to moderate allergic reactions that may be controlled by administering premedications such as antihistamines or corticosteroids, slowing the infusion rate, or completely stopping the administration of rhGAA.3   

In IOPD, early initiation of ERT has been shown to significantly improve life expectancy, reduce cardiomegaly, improve cardiac and skeletal muscle functions, and reduce glycogen accumulation.3

The alglucosidase alfa drug, Myozyme®, received US Food and Drug Administration (FDA) approval in 2006 for the treatment of infants and children with Pompe disease, which was followed by the approval of Lumizyme® in 2010 for use in individuals older than 8 years with late-onset Pompe disease. In 2014, FDA approval expanded the age-restricted use of Lumizyme to allow it to be used in patients of all ages.3,4

Limitations of ERT

ERT has improved cardiac function and extended survival times in patients with IOPD. However, patients are not fully cured and residual symptoms remain. Respiratory and swallowing functions are only stabilized. About 30% of patients who received ERT still require assisted ventilation.5

In addition, many patients who receive ERT may develop immune reactions against rhGAA, decreasing the efficacy of the treatment. Thus, all patients must be evaluated to see if they produce cross-reactive immunologic material (CRIM). ERT in patients without any CRIM (or CRIM-negative) usually results in the development of anti-rhGAA antibodies and requires the use of immunomodulatory drugs (such as rituximab combined with mycophenolate mofetil, methotrexate, or sirolimus) early in the treatment and a monthly gamma globulin support to suppress the immune response.

The CRIM status of an individual with Pompe disease can be determined by quantifying GAA protein using an antibody-based method or molecular genetic testing to examine if the GAA mutations (such as null mutations) result in a complete absence of enzyme activity. In CRIM-negative individuals, the administered enzyme is recognized as a foreign protein, resulting in high antibody titers and subsequent clinical worsening. In contrast, CRIM-positive patients who have some amount of GAA protein (even if it is inactive) do not recognize rhGAA as foreign, and the ERT is more effective.3,4

Apart from these limitations, there is a need for higher doses of rhGAA to correct the GAA deficiency; up to 85% of rhGAA is taken up by the liver, limiting the levels that reach the muscle. Further, the recombinant enzyme is also unable to cross the blood-brain barrier and reach the nervous system.5

Moreover, both CRIM-positive and CRIM-negative patients are at risk of severe and detrimental immune responses that may occur due to immunoglobulin E (IgE) antibodies, necessitating the need for infusions to be administered in hospitals.3

Future ERT Studies 

To overcome the limitations of rhGAA therapy, modified rhGAA (avalglucosidase alfa, Neo-GAA) with a higher affinity for M6P receptors is being investigated in a phase 3 clinical study (NCT02782741).6 

Another modified form of rhGAA called ATB200, with M6P and bis-M6P glycan residues, is being studied in combination with chaperones in a clinical trial (NCT03865836).7,8


  1. GAA gene. MedlinePlus. Updated May 20, 2021. Accessed July 27, 2021.
  2. Pompe disease. MedlinePlus. Updated May 20, 2021. Accessed July 27, 2021.
  3. Bay LB, Denzler I, Durand C, et al. Infantile-onset Pompe disease: diagnosis and management. Arch Argent Pediatr. 2019;117(4):271-278. doi:10.5546/aap.2019.eng.271
  4. Leslie N, Bailey L. Pompe disease. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 2007.
  5. Ronzitti G, Collaud F, Laforet P, Mingozzi F. Progress and challenges of gene therapy for Pompe disease. Ann Transl Med. 2019;7(13):287. doi:10.21037/atm.2019.04.67
  6. Study to compare the efficacy and safety of enzyme replacement therapies avalglucosidase alfa and alglucosidase alfa administered every other week in patients with late-onset Pompe disease who have not been previously treated for Pompe disease. ClinicalTrials.gov. May 25, 2016. Updated April 8, 2021. Accessed July 27, 2021.
  7. Expanded access for ATB200/AT2221 for the treatment of Pompe disease. ClinicalTrials.gov. March 7, 2019. Updated April 12, 2021. Accessed July 27, 2021.
  8. PROPEL study – a study comparing ATB200/AT2221 with alglucosidase/placebo in adult subjects With LOPD. ClinicalTrials.gov. November 2, 2018. Updated February 15, 2021. Accessed July 27, 2021.

Reviewed by Debjyoti Talukdar, MD, on 7/27/2021.