Failure of Autophagy in Pompe Disease.

Autophagy is an evolutionarily conserved lysosome-dependent degradation of cytoplasmic constituents. The system operates as a critical cellular pro-survival mechanism in response to nutrient deprivation and a variety of stress conditions. On top of that, autophagy is involved in maintaining cellular homeostasis through selective elimination of worn-out or damaged proteins and organelles.

Skeletal muscle effects of antisense oligonucleotides targeting glycogen synthase 1 in a mouse model of Pompe disease.

Pompe disease (PD) is a progressive myopathy caused by the aberrant accumulation of glycogen in skeletal and cardiac muscle resulting from the deficiency of the enzyme acid alpha-glucosidase (GAA). Administration of recombinant human GAA as enzyme replacement therapy (ERT) works well in alleviating the cardiac manifestations of PD but loses sustained benefit in ameliorating the skeletal muscle pathology. The limited efficacy of ERT in skeletal muscle is partially attributable to its inability to curb the accumulation of new glycogen produced by the muscle enzyme glycogen synthase 1 (GYS1).

AAV-mediated delivery of secreted acid α-glucosidase with enhanced uptake corrects neuromuscular pathology in Pompe mice.

Gene therapy is under advanced clinical development for several lysosomal storage disorders. Pompe disease, a debilitating neuromuscular illness affecting infants, children, and adults with different severity, is caused by a deficiency of lysosomal glycogen-degrading enzyme acid α-glucosidase (GAA). Here, we demonstrated that adeno-associated virus-mediated (AAV-mediated) systemic gene transfer reversed glycogen storage in all key therapeutic targets - skeletal and cardiac muscles, the diaphragm, and the central nervous system - in both young and severely affected old Gaa-knockout mice.

Nutritional co-therapy with 1,3-butanediol and multi-ingredient antioxidants enhances autophagic clearance in Pompe disease.

Alglucosidase alpha is an orphan drug approved for enzyme replacement therapy (ERT) in Pompe disease (PD); however, its efficacy is limited in skeletal muscle because of a partial blockage of autophagic flux that hinders intracellular trafficking and enzyme delivery. Adjunctive therapies that enhance autophagic flux and protect mitochondrial integrity may alleviate autophagic blockage and oxidative stress and thereby improve ERT efficacy in PD. In this study, we compared the benefits of ERT combined with a ketogenic diet (ERT-KETO), daily administration of an oral ketone precursor (1,3-butanediol; ERT-BD), a multi-ingredient antioxidant diet (ERT-MITO; CoQ10, α-lipoic acid, vitamin E, beetroot extract, HMB, creatine, and citrulline), or co-therapy with the ketone precursor and multi-ingredient antioxidants (ERT-BD-MITO) on skeletal muscle pathology in GAA-KO mice.

Chemoenzymatic glycan-selective remodeling of a therapeutic lysosomal enzyme with high-affinity M6P-glycan ligands. Enzyme substrate specificity is the name of the game.

Functionalization of therapeutic lysosomal enzymes with mannose-6-phosphate (M6P) glycan ligands represents a major strategy for enhancing the cation-independent M6P receptor (CI-MPR)-mediated cellular uptake, thus improving the overall therapeutic efficacy of the enzymes. However, the minimal high-affinity M6P-containing -glycan ligands remain to be identified and their efficient and site-selective conjugation to therapeutic lysosomal enzymes is a challenging task. We report here the chemical synthesis of truncated M6P-glycan oxazolines and their use for enzymatic glycan remodeling of recombinant human acid α-glucosidase (rhGAA), an enzyme used for treatment of Pompe disease which is a disorder caused by a deficiency of the glycogen-degrading lysosomal enzyme.

Impaired autophagy: The collateral damage of lysosomal storage disorders.

Lysosomal storage disorders (LSDs), which number over fifty, are monogenically inherited and caused by mutations in genes encoding proteins that are involved in lysosomal function. Lack of the functional protein results in storage of a distinctive material within the lysosomes, which for years was thought to determine the pathophysiology of the disorder. However, our current view posits that the primary storage material disrupts the normal role of the lysosome in the autophagic pathway resulting in the secondary storage of autophagic debris.

Pompe Disease: New Developments in an Old Lysosomal Storage Disorder.

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.

Enzyme Replacement Therapy Can Reverse Pathogenic Cascade in Pompe Disease.

Pompe disease, a deficiency of glycogen-degrading lysosomal acid alpha-glucosidase (GAA), is a disabling multisystemic illness that invariably affects skeletal muscle in all patients. The patients still carry a heavy burden of the disease, despite the currently available enzyme replacement therapy. We have previously shown that progressive entrapment of glycogen in the lysosome in muscle sets in motion a whole series of "extra-lysosomal" events including defective autophagy and disruption of a variety of signaling pathways.

SnapShot: Lysosomal Storage Diseases.

Lysosomal storage diseases (LSDs) represent a group of monogenic inherited metabolic disorders characterized by the progressive accumulation of undegraded substrates inside lysosomes, resulting in aberrant lysosomal activity and homeostasis. This SnapShot summarizes the intracellular localization and function of proteins implicated in LSDs. Common aspects of LSD pathogenesis and the major current therapeutic approaches are noted.

Pros and cons of different ways to address dysfunctional autophagy in Pompe disease.

Autophagy is a major intracellular self-digestion process that brings cytoplasmic materials to the lysosome for degradation. Defective autophagy has been linked to a broad range of human disorders, including cancer, diabetes, neurodegeneration, autoimmunity, cardiovascular diseases, and myopathies. In Pompe disease, a severe neuromuscular disorder, disturbances in autophagic process manifest themselves as progressive accumulation of undegraded cellular debris in the diseased muscle cells.

Improved efficacy of a next-generation ERT in murine Pompe disease.

Pompe disease is a rare inherited disorder of lysosomal glycogen metabolism due to acid α-glucosidase (GAA) deficiency. Enzyme replacement therapy (ERT) using alglucosidase alfa, a recombinant human GAA (rhGAA), is the only approved treatment for Pompe disease. Although alglucosidase alfa has provided clinical benefits, its poor targeting to key disease-relevant skeletal muscles results in suboptimal efficacy.

Intravenous Injection of an AAV-PHP.B Vector Encoding Human Acid α-Glucosidase Rescues Both Muscle and CNS Defects in Murine Pompe Disease.

Pompe disease, a severe and often fatal neuromuscular disorder, is caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). The disease is characterized by the accumulation of excess glycogen in the heart, skeletal muscle, and CNS. Currently approved enzyme replacement therapy or experimental adeno-associated virus (AAV)-mediated gene therapy has little effect on CNS correction.

Pompe Disease: From Basic Science to Therapy.

Pompe disease is a rare and deadly muscle disorder. As a clinical entity, the disease has been known for over 75 years. While an optimist might be excited about the advances made during this time, a pessimist would note that we have yet to find a cure.

Therapeutic Benefit of Autophagy Modulation in Pompe Disease.

The complexity of the pathogenic cascade in lysosomal storage disorders suggests that combination therapy will be needed to target various aspects of pathogenesis. The standard of care for Pompe disease (glycogen storage disease type II), a deficiency of lysosomal acid alpha glucosidase, is enzyme replacement therapy (ERT). Many patients have poor outcomes due to limited efficacy of the drug in clearing muscle glycogen stores.

Novel degenerative and developmental defects in a zebrafish model of mucolipidosis type IV.

Mucolipidosis type IV (MLIV) is a lysosomal storage disease characterized by neurologic and ophthalmologic abnormalities. There is currently no effective treatment. MLIV is caused by mutations in MCOLN1, a lysosomal cation channel from the transient receptor potential (TRP) family.

Modulation of mTOR signaling as a strategy for the treatment of Pompe disease.

Mechanistic target of rapamycin (mTOR) coordinates biosynthetic and catabolic processes in response to multiple extracellular and intracellular signals including growth factors and nutrients. This serine/threonine kinase has long been known as a critical regulator of muscle mass. The recent finding that the decision regarding its activation/inactivation takes place at the lysosome undeniably brings mTOR into the field of lysosomal storage diseases.

TFEB and TFE3: Linking Lysosomes to Cellular Adaptation to Stress.

In recent years, our vision of lysosomes has drastically changed. Formerly considered to be mere degradative compartments, they are now recognized as key players in many cellular processes. The ability of lysosomes to respond to different stimuli revealed a complex and coordinated regulation of lysosomal gene expression.