{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:52:36Z","timestamp":1788346356566,"version":"build-2803163510"},"reference-count":42,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T00:00:00Z","timestamp":1746489600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Eurostars-2 joint program","award":["E!113321_CHAPERONE"],"award-info":[{"award-number":["E!113321_CHAPERONE"]}]},{"name":"Eurostars-2 joint program","award":["310030-214903"],"award-info":[{"award-number":["310030-214903"]}]},{"name":"Eurostars-2 joint program","award":["320030-227541"],"award-info":[{"award-number":["320030-227541"]}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["E!113321_CHAPERONE"],"award-info":[{"award-number":["E!113321_CHAPERONE"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["310030-214903"],"award-info":[{"award-number":["310030-214903"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["320030-227541"],"award-info":[{"award-number":["320030-227541"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Variants in the GBA1 gene, encoding the lysosomal enzyme glucosylceramidase beta 1 (GCase), are linked to Parkinson\u2019s 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\u00ae), 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\u2019 mechanism of action and highlight their therapeutic potential for GCase-related disorders, including GD, PD, and Dementia with Lewy Bodies.<\/jats:p>","DOI":"10.3390\/ijms26094392","type":"journal-article","created":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T04:28:22Z","timestamp":1746505702000},"page":"4392","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Allosteric Modulation of GCase Enhances Lysosomal Activity and Reduces ER Stress in GCase-Related Disorders"],"prefix":"10.3390","volume":"26","author":[{"given":"Ilaria","family":"Fregno","sequence":"first","affiliation":[{"name":"Faculty of Biomedical Sciences, Institute for Research in Biomedicine, Universit\u00e0 Della Svizzera Italiana, CH-6500 Bellinzona, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"P\u00e9rez-Carmona","sequence":"additional","affiliation":[{"name":"Gain Therapeutics, Sucursal en Espa\u00f1a, Parc Cient\u00edfic de Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7915-5616","authenticated-orcid":false,"given":"Mikhail","family":"Rudinskiy","sequence":"additional","affiliation":[{"name":"Faculty of Biomedical Sciences, Institute for Research in Biomedicine, Universit\u00e0 Della Svizzera Italiana, CH-6500 Bellinzona, Switzerland"},{"name":"Department of Biology, Swiss Federal Institute of Technology; CH-8093 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Sold\u00e0","sequence":"additional","affiliation":[{"name":"Faculty of Biomedical Sciences, Institute for Research in Biomedicine, Universit\u00e0 Della Svizzera Italiana, CH-6500 Bellinzona, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J.","family":"Bergmann","sequence":"additional","affiliation":[{"name":"Faculty of Biomedical Sciences, Institute for Research in Biomedicine, Universit\u00e0 Della Svizzera Italiana, CH-6500 Bellinzona, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Ruano","sequence":"additional","affiliation":[{"name":"Gain Therapeutics, Sucursal en Espa\u00f1a, Parc Cient\u00edfic de Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2793-1545","authenticated-orcid":false,"given":"Aida","family":"Delgado","sequence":"additional","affiliation":[{"name":"Gain Therapeutics, Sucursal en Espa\u00f1a, Parc Cient\u00edfic de Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2239-6670","authenticated-orcid":false,"given":"Elena","family":"Cubero","sequence":"additional","affiliation":[{"name":"Gain Therapeutics, Sucursal en Espa\u00f1a, Parc Cient\u00edfic de Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manolo","family":"Bellotto","sequence":"additional","affiliation":[{"name":"GT Gain Therapeutics SA, CH-6900 Lugano, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9582-7429","authenticated-orcid":false,"given":"Ana Mar\u00eda","family":"Garc\u00eda-Collazo","sequence":"additional","affiliation":[{"name":"Gain Therapeutics, Sucursal en Espa\u00f1a, Parc Cient\u00edfic de Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7636-5829","authenticated-orcid":false,"given":"Maurizio","family":"Molinari","sequence":"additional","affiliation":[{"name":"Faculty of Biomedical Sciences, Institute for Research in Biomedicine, Universit\u00e0 Della Svizzera Italiana, CH-6500 Bellinzona, Switzerland"},{"name":"School of Life Sciences, \u00c9cole Polytechnique F\u00e9d\u00e9rale de Lausanne, CH-1015 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.biocel.2018.05.008","article-title":"Adipose-derived mesenchymal stem cells release microvesicles with procoagulant activity","volume":"100","author":"Fiedler","year":"2018","journal-title":"Int. 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