Enzyme replacement therapy (ERT) has the potential to change the prognosis of Pompe disease (PD). It represents the current standard of care for the disease. Various investigational therapies for PD are in development, including next-generation ERT as part of late-stage clinical development. In a previous study, the recombinant acid alpha-glucosidase (rhGAA) recommended dose of 20 mg/kg was administered intravenously every other week to patients with infantile-onset Pompe disease (IOPD), along with higher dose regimens (up to 40 mg/kg). The dosage for rhGAA shows a higher threshold for treating PD as it corrects GAA deficiency in patients with PD. Muscle targeting is limited as the liver takes up the majority of the rhGAA. Cardiac and respiratory improvement is observed in patients treated with ERT and recombinant human GAA.

Gene therapy has the potential to change the way PD is treated. Several gene therapies for treating PD were tested in the preclinical phase using an animal model. They offer therapeutic options for both infantile- and late-onset Pompe disease.¹

Modulation of mTOR Signaling as a Treatment Modality

A highly conservative threonine/serine kinase, mechanistic target of rapamycin (mTOR), has the potential to form multiprotein complexes – mTOR complex 1 (TORC1) and mTOR complex 2 (TORC2). The TORC1 complex is sensitive to rapamycin, as it responds to multiple signals when activated. mTOR has the potential to change the cell metabolism to multiple signals when it is activated. The mTOR signaling pathway is involved in the muscle wasting seen in Pompe disease because there is dysregulation of mTOR signaling in the diseased muscle cells. mTOR can act as a therapeutic intervention in potential sites, and it can be reactivated in the whole muscle. In murine models, the reactivation of mTOR yielded the reversal of atrophy and the removal of autophagic buildup. Moreover, mTOR signaling can be reserved with arginine, which might be a targeted therapy for metabolic, neuromuscular, and lysosomal disorders.²

Stop Codon Readthrough Therapy

Nonsense-mediated decay (NMD) is triggered by ribosomes due to the recognition of premature termination codons (PTCs) generating nonsense mutations. NMD is an evolutionary preserved mechanism of cellular control and surveillance that can lead to mRNA degradation. Previous studies have shown that a partially complementary tRNA binds to a premature stop codon in less than 1% of cases. It leads to insertion of a random amino acid, which has the potential to produce stable but abnormal protein. This mechanism of stop codon readthrough or suppression of termination can be exploited for nonsense suppression therapy.³

Chaperone Therapy as an Alternate Treatment Modality

Chaperone therapy can act as an alternative treatment modality for PD compared to conventional ERT. Research studies have shown that the transport and stability of the GAA enzyme is affected by mutations in PD. However, mutations do not affect the catalytic or synthesis functions of the GAA enzyme. Misfolded or unstable proteins in the endoplasmic reticulum (ER) can be fixed using chemical chaperones. As per in vitro studies conducted, mutated GAA species can be transported from the ER to the lysosomes using chemical chaperones like N-butyldeoxynojirimycin (NB-DNJ) and deoxynojirimycin (DNJ). The effect of such chaperones is mutation-specific, and is thus specific to the patient. It can lead to endogenous processing of the enzyme at the natural site. Enhanced uptake of the enzyme in the tissue has the potential to reach the skeletal muscle.⁴

Gene Therapy for Treating PD

Gene therapy can act as an alternate modality to ERT and chaperone therapy. It involves incorporating an active copy of GAA cDNA into the affected tissues through a modified virus. Inborn genetic mutation is compensated by gene therapy because it allows a continuous internal source of enzyme. The possibility of gene therapy has been explored pre-clinically in both in vivo and in vitro models. In vitro studies have shown efficient intracellular accumulation of the precursor form of GAA in GAA-deficient fibroblasts derived from patients with the infantile form of PD. The GAA precursor is secreted by the transduced GAA-deficient fibroblasts in the culture medium after it is taken up by recipient cells. It can lead to a reduction in the lysosomal glycogen content of these cells. GAA-deficient cells can be rescued by neighboring transduced cells through mannose-6-phosphate receptor-mediated uptake of adenoviral-expressed GAA.⁴

Correction of Glycogen Accumulation in Skeletal Muscle

Compared to other lysosomal storage disorders (LSDs), it is challenging to correct glycogen accumulation in the skeletal muscle of patients with PD using ERT. Affected cells with glycogen accumulation have immediate access to the intravenously administered enzymes. The blood-muscle barrier, consisting of interstitial tissues, basement membrane, and endothelial cells, can be separated from the circulatory system by the muscle cells. In PD, the administered enzyme may encounter functional and physical barriers along with non-productive sinks. Moreover, half of the total body weight in healthy adults consists of skeletal muscle. Clearance of lysosomal glycogen from larger tissues is a challenge, as it questions the dosage of enzymes required to treat PD effectively. Glycogen accumulation in the skeletal muscle can complicate the treatment of the metabolic defect because there are biochemical differences between muscle fibers.⁵ The short half-life of GAA can limit the potential of ERT. Experimental therapies, like liver-specific expression of GAA with recombinant AAV8 vector expressing human GAA under the transcriptional control of a liver-specific promoter (8-LSPhGAA12/AAV2), can suppress the antibody response that interferes with the uptake of GAA and continually secrete GAA in the blood, improving their efficacy.⁶


  1. 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
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  4. Geel TM, McLaughlin PMJ, de Leij LFMH, Ruiters MHJ, Niezen-Koning KE. Pompe disease: current state of treatment modalities and animal models. Mol Genet Metab. 2007;92(4):299-307. doi:10.1016/j.ymgme.2007.07.009
  5. McVie-Wylie AJ, Lee KL, Qiu H, et al. Biochemical and pharmacological characterization of different recombinant acid α-glucosidase preparations evaluated for the treatment of Pompe disease. Mol Genet Metab. 2008;94(4):448-455. doi:10.1016/j.ymgme.2008.04.009
  6. Han SO, Ronzitti G, Arnson B, et al. Low-dose liver-targeted gene therapy for Pompe disease enhances therapeutic efficacy of ERT via immune tolerance induction. Mol Ther Methods Clin Dev. 2017;4:126-136. doi:10.1016/j.omtm.2016.12.010

Reviewed by Harshi Dhingra, MD, on 8/27/2021.