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Molinari_2025_MDPI_ijms_Allosteric Modulation
Journal article

Allosteric modulation of GCase enhances lysosomal activity and reduces ER stress in GCase-related disorders

  • Fregno, Ilaria ORCID Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Pérez-Carmona, Natalia Gain Therapeutics, Sucursal en España, Parc Científic de Barcelona, Spain
  • Rudinskiy, Mikhail ORCID Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Department of Biology, Swiss Federal Institute of Technology, Zurich, Switzerland
  • Solda, Tatiana Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Bergmann, Timothy J. ORCID Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Ruano, Ana Gain Therapeutics, Sucursal en España, Parc Científic de Barcelona, Spain
  • Delgado, Aida Gain Therapeutics, Sucursal en España, Parc Científic de Barcelona, Spain
  • Cubero, Elena Gain Therapeutics, Sucursal en España, Parc Científic de Barcelona, Spain
  • Bellotto, Manolo GT Gain Therapeutics SA, Lugano, Switzerland
  • García-Collazo, Ana María Gain Therapeutics, Sucursal en España, Parc Científic de Barcelona, Spain
  • Molinari, Maurizio ORCID Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - School of Life Sciences, École Polytechnique Fédérale de Lausanne, Switzerland
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  • 2025
Published in:
  • IJMS. - 2025, vol. 26, no. 9, p. 4392
Parkinson’s disease
Gaucher disease
Glucosylceramidase beta 1 (GCase)
Lysosomal storage disorders
Structurally targeted allosteric regulators (STARs)
Site-directed enzyme enhancement therapy (SEE-Tx)
Pharmacological chaperones
Protein misfolding
Lysosomal dysfunction
Allosteric modulation
English Variants in the GBA1 gene, encoding the lysosomal enzyme glucosylceramidase beta 1 (GCase), are linked to Parkinson’s disease (PD) and Gaucher disease (GD). Heterozygous variants increase PD risk, while homozygous variants lead to GD, a lysosomal storage disorder. Some GBA1 variants impair GCase maturation in the endoplasmic reticulum, blocking lysosomal transport and causing glucosylceramide accumulation, which disrupts lysosomal function. This study explores therapeutic strategies to address these dysfunctions. Using Site-directed Enzyme Enhancement Therapy (SEE-Tx®), two structurally targeted allosteric regulators (STARs), GT-02287 and GT-02329, were developed and tested in GD patient-derived fibroblasts with relevant GCase variants. Treatment with GT-02287 and GT-02329 improved the folding of mutant GCase, protected the GCaseLeu444Pro variant from degradation, and facilitated the delivery of active GCase to lysosomes. This enhanced lysosomal function and reduced cellular stress. These findings validate the STARs’ mechanism of action and highlight their therapeutic potential for GCase-related disorders, including GD, PD, and Dementia with Lewy Bodies.
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Language
  • English
Classification
Medicine
License
CC BY
Open access status
gold
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Persistent URL
https://n2t.net/ark:/12658/srd1332021
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