gene therapy

We already have a glimpse of what the next wave of therapies for Pompe disease (PD) looks like: gene therapy. Gene therapy aims to go beyond conventional alpha-glucosidase (GAA) replacement in causing the lasting secretion of GAA at therapeutic levels.

“There is a lot of excitement and expectations about the next wave of therapies for [Pompe disease], dictated by the fact that the condition remains an unmet medical need,“ Colella and Mingozzi wrote in a paper titled “Gene Therapy for Pompe disease: The Time Is Now.” ”The entire Pompe community, scientists, clinicians and trial participants need to understand the challenges and opportunities ahead and work together synergistically to improve the standard of care for the disease.” 

Limitations of the Current Standard of Care 

Currently, the standard of care for PD patients consists of enzyme replacement therapy (ERT), ie, the replacement of GAA via intravenous (IV) infusion. When ERT was introduced, it represented a major medical breakthrough. This therapeutic approach makes sense, considering the main factor driving PD pathology is the lack of the GAA enzyme. Studies have indicated that it achieves modest success in alleviating the symptoms experienced by PD patients.

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Read more about PD epidemiology 

However, some limitations of ERT remain. For example, it does not cross the blood-brain barrier efficiently. This means that while ERT can delay the onset of skeletal muscle weakness, it does not have a significant effect on the neurological manifestations of PD. The partial efficacy of ERT in this sense is driving medical researchers to find a better therapeutic approach that confers benefits to the central nervous system (CNS) as well. 

Colella and Mingozzi wrote, “Despite the obvious benefits in terms of survival in [infantile-onset Pompe disease] and stabilization of disease progression in [late-onset Pompe disease], ERT does not represent a definitive solution to PD. This conclusion arises from recent reviews of many clinical studies in both IOPD and LOPD subjects.” 

The effects of ERT are significantly variable in patients with LOPD, and a significant proportion of patients still become dependent on locomotor and respiratory support eventually, despite being on ERT. This is also in spite of the fact that the formation of neutralizing anti-rhGAA is a rare event.

Salabarria and colleagues wrote, “Although IV delivery [of GAA] is a successful strategy in mitigating the phenotype and underlying neuropathology of the disease, it faces crucial challenges regarding 1) cost and availability of high amount of product and 2) the host immune response against the vector capsid protein and transgene.”

In addition, ERT requires lifelong, regular IV infusions. This imposes a significant burden on PD patients and is a contributing reason for its high costs. 

A New Approach With New Targets 

The limitations of conventional ERT is the pistol shot for the exploration of gene therapy for the treatment of PD. At present, most studies involving gene therapy for PD have made use of Gaa−/− mice. 

For example, one study investigated the efficacy of a single IV injection of an adenoviral vector containing the cytomegalovirus (CMV) enhancer/promoter that drives GAA cDNA expression. This resulted in the liver secreting the human GAA precursor enzyme, which led to high levels of GAA activity in the plasma, with glycogen correction observed in the skeletal muscle, smooth muscle, and the heart. 

In a review published in Biomedicines, Unnisa and colleagues explained, “The predominant gene-transfer delivery systems investigated in preclinical and clinical settings are viral-based vectors designed to be utilized in in vivo and ex vivo gene therapies, which in the case of Pompe disease, is mainly centered around adeno-associated viral (AAV) vectors for in vivo applications and lentiviral (LV) vectors for ex vivo hematopoietic stem cell gene therapy.” 

Read more about PD treatment 

Gene therapy for PD has 3 main targets: the muscles, the liver, and the CNS. 

For muscle-directed delivery, the goal is to resolve cardiomyopathy and improve diaphragmatic respiratory function. Studies on mouse models have demonstrated glycogen clearance and increased GAA activity via intramuscular injection of AAV vectors encoding human GAA. 

Liver-directed gene therapy aims to take advantage of the high biodistribution of AAV vectors to the liver, which allows for lower doses of AAV.

“The liver is able to secrete high levels of many serum proteins and this is an advantage for high-level expression of GAA, especially when engineered to enhance secretion,“ Salabarria and colleagues wrote. “Additionally, liver-directed expression can lead to immune tolerance induction.”

CNS-directed AAV gene therapy aims to resolve the CNS symptoms in PD. The abnormal glycogen accumulation in motor neurons in PD often leads to neuromuscular dysfunction. A study involving the injection of an AAV vector encoding the GAA protein in the C3-C4 spinal level of GAA-/- mice successfully attenuated glycogen levels in the cervical ventral horn and the spinal cord, which later manifested as respiratory function improvement.

“This emphasizes that the therapy needs to be targeted to both the CNS and skeletal muscles to effectively treat Pompe disease,” Unnisa and colleagues commented. 

Ultimately, gene therapy represents the way forward for PD management because the current standard of PD therapy (ie, ERT) does not go far enough to resolve the clinical manifestations of PD. The grand goal of this gene therapy is to increase GAA to therapeutic levels and for that increase to be sustained permanently. With continued research, we might soon see the day when gene therapy becomes routine in PD management. 


Unnisa Z, Yoon JK, Schindler JW, Mason C, van Til NP. Gene therapy developments for Pompe diseaseBiomedicines. 2022; 10(2):302. doi:10.3390/biomedicines10020302

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

Salabarria SM, Nair J, Clement N, Smith BK, Raben N, et al. Advancements in AAV-mediated gene therapy for Pompe disease. J Neuromuscul Dis. 2020;7(1):15-31. doi:10.3233/JND-190426