2026-08-11 | Chemical tools for inhibition and activity-based profiling of glucocerebrosidase in vitro and in vivo.

Deficiencies in glucocerebrosidase (GCase) are associated with Parkinson's disease (PD). The mechanistic basis of this association is being intensively investigated, and new treatments are being developed aiming to boost brain GCase activity in patients. Despite the importance of GCase in PD, studies are hampered by the continued reliance on weak and non-selective inhibitors like conduritol B epoxide. Here, we report easily prepared and selective irreversible inhibitors and complementary fluorescent activity-based probes (ABPs), along with straightforward methods to inhibit and/or monitor GCase activity. Robust characterization shows that compound CAz-5c selectively inactivates GCase in vitro, in live cells, and in vivo-including GCase in the brains of live mice, at low doses, overcoming a limitation of previously reported inhibitors. Collectively, these tools can be used to generate titratable chemical models of neuropathic GCase deficiency in animals with various genetic backgrounds with unrivaled molecular precision.

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2026-08-05 | GAUCHER`S DISEASE: DIAGNOSIS, ENZYME REPLACEMENT THERAPY, AND PHARMACEUTICAL FORMULATIONS IN TREATMENT– A COMPREHENSIVE REVIEW

Gaucher's disease (GD) is the most common lysosomal storage disorder caused by mutations in the GBA1 gene, resulting in deficiency of the enzyme β-glucocerebrosidase. This leads to the accumulation of glucosylceramide within macrophages, causing progressive involvement of the liver, spleen, bone marrow, and, in severe cases, the central nervous system. Clinical manifestations include hepatosplenomegaly, anemia, thrombocytopenia, skeletal abnormalities, and neurological complications. Recent advances in diagnostic techniques, including enzyme assays, molecular genetic testing, and biomarker analysis, have improved early detection and disease monitoring. Enzyme replacement therapy (ERT) remains the standard treatment, while substrate reduction therapy (SRT) provides an alternative for selected patients. Advances in pharmaceutical formulations, including liposomal and nanoparticle-based drug delivery systems, have enhanced therapeutic efficacy and patient compliance. Emerging approaches such as gene therapy offer promising prospects for long-term disease management. This review summarizes the epidemiology, pathophysiology, clinical features, diagnosis, current treatment strategies, and recent pharmaceutical advancements in Gaucher's disease, highlighting future directions for improving patient outcomes.

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2026-07-31 | 4-Dehydroxymethyl-4-C-biphenyl-DAB derivatives: introduction of a biphenyl group at the C4 position shifts the binding selectivity, resulting in improved affinity for lysosomal acid β-glucocerebrosidase.

Pharmacological chaperones can enhance the stability of the three-dimensional structure by reversibly binding to the active site of mutant enzymes, thereby promoting maturation within the cell and transport to the lysosome. This study provides an example of a high-affinity ligand design strategy for lysosomal acid β-glucocerebrosidase (GCase), focusing on introducing a biphenyl substituent at the C4 position of 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) in place of the native hydroxymethyl group. The introduction of a p-CF3-biphenyl group at the C4 position shifted the binding selectivity of DAB from α-glucosidase to β-glucosidase while simultaneously increasing binding affinity by 4289-fold compared to DAB, exhibiting nanomolar affinity (Ki = 0.045 μM). These findings suggest a novel possibility that contradicts the conventional view that modification of the hydroxymethyl group at the C4 position of the pyrrolidine ring inevitably leads to loss of sugar recognition ability and a consequent decrease in binding affinity. The docking models and molecular dynamics simulations showed that para-trifluoromethyl substitution restricts the mobility of the B-ring of the biphenyl moiety within the hydrophobic pocket of GCase. This interaction of the para-trifluoromethyl group and the hydrophobic pocket stabilises the active site architecture and markedly suppresses dynamic fluctuations of loop 1 and loop 2 compared with fluctuations observed in the isofagomine complex, thereby contributing to enhanced thermodynamic stabilisation of the enzyme. 4-Dehydroxymethyl-4-C-(p-CF3-biphenyl)-DAB (6e) dose dependently increased intracellular GCase activity in V394L and L444P mutant cells. It is noteworthy that the effective dose was about 10-fold lower than that for isofagomine. Therefore, 4-dehydroxymethyl-4-C-(p-CF3-biphenyl)-DAB (6e) is expected to increase intracellular mutant enzyme activity and may represent a useful therapeutic option for the treatment of Gaucher disease.

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2026-07-09 | Extracellular vesicles as minimally invasive biomarkers and therapeutic platforms in rare neurological diseases.

Rare neurological diseases (RND) represent a growing but underrecognized global health burden, particularly in aging populations in whom clinical manifestations appear later in life, resulting in substantial morbidity, reduced quality of life, and increased mortality. Advances in understanding and treating these diseases have been hindered by low prevalence, phenotypic heterogeneity, and complex molecular mechanisms. Importantly, shared genetic and mechanistic links between rare and common neurodegenerative disorders, such as GBA1 (Glucosylceramidase Beta 1) gene variant-associated Gaucher disease (GD) and Parkinson's disease (PD), highlight convergent biological pathways that may be leveraged for biomarker discovery and therapeutic innovation. Notably, individuals heterozygous for pathogenic GBA1 variants, historically considered asymptomatic carriers, are now recognized to have an increased lifetime risk of developing PD and related synucleinopathies. This emerging evidence indicates that even single-allele variants can confer long-term neurological risk, reinforcing the continuum between rare monogenic disorders and more common neurodegenerative diseases. Extracellular Vesicles (EVs) have emerged as a promising, minimally invasive platform for advancing RND research, although translation remains limited by source specificity, vesicle heterogeneity, and incomplete clinical validation. By encapsulating proteins, lipids, and nucleic acids that reflect their cellular origin and disease state, EVs offer unique opportunities for early diagnosis, disease stratification, longitudinal monitoring, and assessment of treatment responses. In this review, we summarize fundamental aspects of EV biology and critically evaluate recent advances in EV-based biomarker discovery for RND, informed by translational insights from more prevalent neurodegenerative conditions. We further discuss the therapeutic potential of EVs, emphasizing their intrinsic biocompatibility, their reported capacity in selected preclinical settings to traverse biological barriers, including the blood-brain barrier, and their versatility as carriers for neuroprotective and gene-modifying cargo. Finally, we address key technical and translational challenges, including isolation, characterization, scalability, and regulatory considerations that currently limit clinical adoption. Collectively, this review highlights emerging opportunities and outlines an integrative translational perspective for EV-based diagnostic and therapeutic strategies into research and clinical paradigms for aging individuals affected by RND.

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2026-07-08 | Long-Term Outcomes of Enzyme Replacement Therapy in Indian Patients with Gaucher Disease - A Multicentric Study.

To evaluate the short- and long-term clinical and laboratory outcomes of Enzyme Replacement Therapy (ERT) in Indian patients with Gaucher disease (GD) and to identify factors influencing the therapeutic response. This retrospective, multicentre cohort study included 204 patients with confirmed GD across 13 Indian centres. Eligible participants had received at least one year of ERT and provided both baseline and follow-up data. Patients were stratified by splenectomy status. Longitudinal outcomes assessed over 1-5, 10, and 15 y included hemoglobin levels, platelet counts, liver and spleen volumes, chitotriosidase activity, bone pain, bone mineral density (BMD), and height/weight Z-scores. Subgroup analyses evaluated the impact of age at ERT initiation, GD subtype, genotype, and baseline disease severity. Of the 204 patients, 173 were non-splenectomised and 31 were post-splenectomy; notably, 136 (66.7%) presented with the GD3 phenotype. The median age at symptom onset, diagnosis, and ERT initiation was 1.5 y, 2.6 y, and 4.3 y respectively. The p.L483P allele was the predominant variant in the cohort. Within the first 1-5 y of ERT, non-splenectomised patients demonstrated marked improvements in hematological parameters, organomegaly, biomarker activity, growth metrics, and bone pain. These improvements were sustained through 10-15 y, characterized by stabilized visceral parameters, persistently low biomarker levels, steady growth, and a low incidence of new skeletal complications. Early initiation of ERT was associated with a greater magnitude of hematological response as early as 1 y. ERT facilitates rapid clinical and laboratory improvements within 1-5 y, with benefits sustained over 10-15 y in Indian GD patients. Despite significant diagnostic delays and the advanced stage of disease at presentation common in this population, long-term outcomes remain highly favourable. Early initiation of ERT is critical for optimizing treatment response and preventing irreversible sequelae.

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