Correction of oxidative stress enhances enzyme replacement therapy in Pompe disease. Issue 11 (4th October 2021)

• Record Type: Journal Article
• Authors: Tarallo, Antonietta; Damiano, Carla; Strollo, Sandra; Minopoli, Nadia; Indrieri, Alessia; Polishchuk, Elena; Zappa, Francesca; Nusco, Edoardo; Fecarotta, Simona; Porto, Caterina; Coletta, Marcella; Iacono, Roberta; Moracci, Marco; Polishchuk, Roman; Medina, Diego Luis; Imbimbo, Paola; Monti, Daria Maria; De Matteis, Maria Antonietta; Parenti, Giancarlo
• Is Part Of: EMBO molecular medicine. Volume 13:Issue 11(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-10-04
• Subjects: alpha‐glucosidase -- enzyme replacement therapy -- N‐acetylcysteine -- oxidative stress -- Pompe disease; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.202114434
• Languages: English
• ISSNs: 1757-4676

Abstract

Abstract: Pompe disease is a metabolic myopathy due to acid alpha‐glucosidase deficiency. In addition to glycogen storage, secondary dysregulation of cellular functions, such as autophagy and oxidative stress, contributes to the disease pathophysiology. We have tested whether oxidative stress impacts on enzyme replacement therapy with recombinant human alpha‐glucosidase (rhGAA), currently the standard of care for Pompe disease patients, and whether correction of oxidative stress may be beneficial for rhGAA therapy. We found elevated oxidative stress levels in tissues from the Pompe disease murine model and in patients' cells. In cells, stress levels inversely correlated with the ability of rhGAA to correct the enzymatic deficiency. Antioxidants (N‐acetylcysteine, idebenone, resveratrol, edaravone) improved alpha‐glucosidase activity in rhGAA‐treated cells, enhanced enzyme processing, and improved mannose‐6‐phosphate receptor localization. When co‐administered with rhGAA, antioxidants improved alpha‐glucosidase activity in tissues from the Pompe disease mouse model. These results indicate that oxidative stress impacts on the efficacy of enzyme replacement therapy in Pompe disease and that manipulation of secondary abnormalities may represent a strategy to improve the efficacy of therapies for this disorder. SYNOPSIS: Enzyme replacement therapy (ERT) with recombinant human alpha‐glucosidase (rhGAA) is currently the standard of care for the treatment of Pompe disease. However, this approach shows important limitations. We have tested whether modulation of oxidative stress may improve the efficacy of ERT. The impairment of the autophagic‐lysosomal pathway in Pompe disease results into accumulation of dysfunctional mitochondria and defective clearance of reactive oxygen species (ROS), thus leading to increased oxidative stress. Oxidative stress is deleterious for the trafficking of the recombinant enzyme used for enzyme replacement therapy through the endocytic pathway. Antioxidants improve the amounts of the mannose‐6‐phosphate receptor available at the plasma membrane and improve recombinant enzyme trafficking to lysosomes. Abstract : Enzyme replacement therapy (ERT) with recombinant human alpha‐glucosidase (rhGAA) is currently the standard of care for the treatment of Pompe disease. However, this approach shows important limitations. We have tested whether modulation of oxidative stress may improve the efficacy of ERT.