Pompe Disease: New Developments in an Old Lysosomal Storage Disorder

Abstract

Pompe disease, also known as glycogen storage disease type II, is caused by the lack or deficiency of a single enzyme, lysosomal acid alpha-glucosidase, leading to severe cardiac and skeletal muscle myopathy due to progressive accumulation of glycogen. The discovery that acid alpha-glucosidase resides in the lysosome gave rise to the concept of lysosomal storage diseases, and Pompe disease became the first among many monogenic diseases caused by loss of lysosomal enzyme activities. The only disease-specific treatment available for Pompe disease patients is enzyme replacement therapy (ERT) which aims to halt the natural course of the illness. Both the success and limitations of ERT provided novel insights in the pathophysiology of the disease and motivated the scientific community to develop the next generation of therapies that have already progressed to the clinic.

Ferroptosis and Its Modulation by Autophagy in Light of the Pathogenesis of Lysosomal Storage Diseases

“…In fact, changes in ferroptosis efficiency arising from modulation of lysosomal activities have been suggested [ 3 ]. As mentioned in the introduction, various therapeutic strategies for LSD have been tested; however, apart from the non-neuronopathic type of Gaucher disease, no abolition of symptoms could be achieved in severe and neuronopathic forms of these diseases, and only partial improvement could be achieved in milder forms [ 51 , 52 , 53 ].…”

Preclinical Research in Glycogen Storage Diseases: A Comprehensive Review of Current Animal Models

“…Clinically, PD can be classified in different subtypes: the classical infantile onset disease (CIOD), the non-classical infantile onset disease (NCIOD) and the late-onset disease (LOD). The CIOD is caused by complete or almost null GAA activity (<1%), and the first symptoms are already present in the first two months of life, including progressive and severe hypertrophic cardiomyopathy, profound muscle weakness and hypotonia, whilst heart and respiratory failure and death might occur during the first 18 months of life [ 31 , 32 , 34 ]. Feeding difficulties, poor weight gain, delayed milestones and respiratory difficulties with superimposed infections are also common in these patients [ 12 , 13 , 14 , 15 , 16 ].…”

“…The LOD is characterized by low levels of GAA activity (up to ~20%) and can present in children, adolescence and adults with proximal muscle weakness, motor and respiratory deficit, although cardiomyopathy is normally not present in these patients [ 16 , 243 ]. Long-term complications such as scoliosis and lumbar hyperlordosis may appear, and many patients become wheelchair dependent and require assisted ventilation [ 31 , 32 ].…”

“…CNS abnormalities and signs of cognitive decline have been reported in chronic CIOD patients treated with ERT [ 37 ]. These limitations have prompted the research to develop more effective second-generation drugs consisting on rhGAA with higher affinity for skeletal muscle cells [ 38 , 39 , 40 , 41 ], and search for alternative and/or adjunct therapies such as substrate reduction therapy, inhibition of autophagy and modulation of mTORC1 signaling, chaperone therapy, stimulation of lysosomal exocytosis and antisense oligonucleotides among others [ 31 , 32 , 36 , 42 , 43 , 44 ].…”

“…The results in this trial showed that rAAV1-hGAA was safe and improved respiratory function [ 45 , 46 , 47 ]. Currently, two successive intramuscular administrations of an AAV9 vector expressing GAA are being evaluated in patients with LOD in a phase 1/2 clinical trial (NCT02240407) [ 32 ]. Additionally, two Phase I clinical trials of AAV vector-mediated liver depot gene therapy have also been initiated (NCT03533673 and NCT04093349) [ 48 ].…”