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Publications

Journal Article Ahead of print

PubMed: 42277847 DOI: 10.1186/s12967-026-08343-3

TRPML1 agonists synergize with enzyme replacement therapy in fibroblasts from Pompe disease patients.

J Transl Med

Authors: Carla Damiano, Antonietta Tarallo, Sandra Strollo, Nadia Minopoli, Anna Valanzano, Antonia Assunto, Maria Rosaria Tuzzi, Nicola Brunetti-Pierri, Andrea Ballabio, Nicolina Cristina Sorrentino, Giancarlo Parenti

Affiliations

  • UOS Research Laboratories and Biobank, AORN Santobono-Pausilipon, Via Posillipo 226, Naples, Italy.
  • Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, Pozzuoli, Italy.
  • Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Via S. Pansini 5, Naples, Italy.
  • Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, Pozzuoli, Italy. Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Via S. Pansini 5, Naples, Italy.
  • School of Advanced Studies, (SSM, Scuola Superiore Meridionale) Genomics and Experimental Medicine Program, University of Naples Federico II, Naples, Italy.
  • Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, Pozzuoli, Italy. Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Via S. Pansini 5, Naples, Italy. School of Advanced Studies, (SSM, Scuola Superiore Meridionale) Genomics and Experimental Medicine Program, University of Naples Federico II, Naples, Italy. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, USA.
  • Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, Pozzuoli, Italy.
  • Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, Pozzuoli, Italy.
  • Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Via S. Pansini 5, Naples, Italy.
  • School of Advanced Studies, (SSM, Scuola Superiore Meridionale) Genomics and Experimental Medicine Program, University of Naples Federico II, Naples, Italy.

Abstract

OBJECTIVE

Pompe disease is a severe and progressive metabolic myopathy caused by pathogenic variants of the GAA gene, deficiency of acid alpha-glucosidase (GAA), and lysosomal glycogen storage. The current standard of treatment for PD is enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA). Despite significant success of ERT in correcting some disease manifestations, limitations of its efficacy have emerged, due to several factors. Poor expression or abnormal intracellular distribution of the cation-independent mannose-6-phosphate receptor (M6PR) at the plasma membrane of specific cells has been identified as one of these factors. Here, we investigated whether activation of Transient Receptor Potential Mucolipin 1 (TRPML1) synergizes with ERT. TRPML1 is a lysosomal ion channel that has been shown to induce multiple effects, including regulation of calcium homeostasis, stimulation of autophagy, activation of lysosomal biogenesis and exocytosis, enhancement of vesicle and membrane trafficking.

METHODS

We studied the effects of two TRPML1 agonists in cultured fibroblasts from Pompe disease patients. Specifically, we analyzed M6PR availability at the plasma membrane of control and mutant cells, level of correction of GAA activity by rhGAA, processing and lysosomal trafficking of the recombinant enzyme.

RESULTS

Treatment with two TRPML1 agonist drugs increased M6PR total amounts and its availability at the plasma membrane and improved M6PR intracellular recycling. The improvements in M6PR distribution translated into better correction of GAA activity in cells incubated with rhGAA and in improved lysosomal trafficking and processing of the recombinant enzyme.

CONCLUSION

These data provide in vitro proof-of-concept evidence supporting the combination of ERT with pharmacological manipulation of secondarily altered M6PR distribution as a strategy to obtain better exposure of cells to therapeutic enzymes.

MeSH

Cells, Genes, Biomedical Research, Cell Membrane, Enzymes, Glycogen Storage Disease Type Ii, Fibroblasts, Enzyme Replacement Therapy, Therapeutics, Membranes, Plasma