Fregno, Ilaria Pérez-Carmona, Natalia Rudinskiy, Mikhail Solda, Tatiana Bergmann, Timothy J. Ruano, Ana Delgado, Aida Cubero, Elena Bellotto, Manolo García-Collazo, Ana María Molinari, Maurizio 2025 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. application/pdf https://n2t.net/ark:/12658/srd1332021 https://susi.usi.ch/global/documents/332021 https://susi.usi.ch/documents/332021/files/Molinari_2025_MDPI_ijms_Allosteric Modulation.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.3390/ijms26094392 info:eu-repo/semantics/altIdentifier/ark/12658/srd1332021 info:eu-repo/semantics/openAccess CC BY 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 info:eu-repo/classification/udc/61 Allosteric modulation of GCase enhances lysosomal activity and reduces ER stress in GCase-related disorders http://purl.org/coar/resource_type/c_6501