RARE DISEASE
Gaucher disease
Gaucher disease
Gaucher disease
Synonyms: Acid beta-glucosidase deficiency, Glucocerebrosidase deficiency
Synonyms: Acid beta-glucosidase deficiency, Glucocerebrosidase deficiency
Synonyms: Acid beta-glucosidase deficiency, Glucocerebrosidase deficiency
Drug discovery
37
drugs
With orphan designations
Overview
Gaucher disease is an autosomal recessive lysosomal storage disorder caused by deficient glucocerebrosidase activity due to GBA1 mutations, resulting in glucocerebroside accumulation. Clinical features include hepatosplenomegaly, cytopenia, bone pathology (osteopenia, fractures), and variable neurological involvement (Types 2/3). Diagnosis combines enzyme assays and genetic testing. Treatment focuses on enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) for systemic symptoms, with no effective neuropathic disease modifiers [1][2][9].
Therapies
Categories: rare genetic diseases, rare inborn errors of metabolism, rare transplant-related disorders
Research Papers
1,825 drug discovery papers about Gaucher disease, with 4 first-in-class and 15 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,825 drug discovery papers about Gaucher disease, with 4 first-in-class and 15 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-08-31 | Conserved water molecules shape the pathogenicity of missense variants in human proteins.
Conserved water molecules (CWMs) are tightly bound solvent molecules that occupy well-defined, recurrent positions in protein structures. Although they are known to influence protein stability, function, and ligand binding, their role in shaping the effects of human missense variants remains largely unexplored. Here, we demonstrate that CWMs are a previously underappreciated determinant of missense variant pathogenicity. By predicting ligand-binding and CWM sites across human PDB structures and mapping missense variants to these sites and the remaining protein surface, we found that pathogenic variants were significantly enriched at CWM sites, whether overlapping or outside other ligand-binding regions. This enrichment exceeded that observed for binding sites as a whole, indicating a broader role for water-mediated interactions in modulating variant effects. To explore a mechanistic basis for this association, we performed molecular dynamics simulations of human lysosomal acid glucosylceramidase (GCase), encoded by GBA1 and implicated in Gaucher disease and Parkinson's disease risk. Selective destabilization of a CWM site in wild-type GCase produced structural and dynamical changes resembling those observed in the pathogenic L444P variant, whereas stabilization of this site in L444P shifted several measures toward wild-type behavior. These results suggest that disruption of a single CWM can contribute to long-range structural remodeling observed in a disease-associated variant. Together, our findings identify CWMs as a novel structural constraint shaping the distribution and effects of pathogenic missense variants. Incorporating water-mediated interactions into structural models provides a generalizable framework for interpreting human genetic variation and its contribution to disease.
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.
2026-06-15 | A 53-week, open-label phase IIIb study of velaglucerase alfa in Chinese patients with type 1 Gaucher disease: Safety, efficacy, and pharmacokinetics.
Velaglucerase alfa is approved in China for treating type 1 Gaucher disease (GD1), but data on its use in Chinese pediatric and adult patients are limited. This study evaluated the safety, efficacy, and pharmacokinetics of velaglucerase alfa in Chinese patients with GD1. This was a phase IIIb, multicenter, open-label, single-arm, 53-week study (NCT05529992). Patients received intravenous velaglucerase alfa (60 U/kg) every 2 weeks. The primary endpoint was the incidence of serious treatment-emergent adverse events (TEAEs). Secondary endpoints evaluated safety (incidence of TEAEs), efficacy (changes in hemoglobin concentrations, platelet counts, liver and spleen volumes [as percent of body weight, % BW]), and quality of life (QoL). Twenty patients were enrolled (treatment-naïve, n = 16; previously treated, n = 4). Four patients experienced 4 serious TEAEs requiring hospitalization; none were treatment-related. Overall, 19 of 20 patients experienced 104 TEAEs, of which 9 were treatment-related (8.7%; all mild). No TEAEs or deaths led to discontinuation of treatment. Mean (SD) improvements in hemoglobin concentrations (baseline, 10.5 g/dL [2.2]; change, +2.3 g/dL [1.3]; +25.5%), platelet counts (baseline, 59.9 × 109/L [23.4]; change, +42.1 × 109/L [27.7]; +82.3%), normalized spleen (baseline, 5.2% BW [2.6]; change, -3.1% BW [1.6]; -58.4%), and liver volume (baseline, 4.6% BW [1.3]; change, -1.1% BW [0.9]; -21.5%) were observed through Week 53. Nineteen of 20 (95.0%) patients reported improved QoL. Velaglucerase alfa was well-tolerated in Chinese patients with GD1, with no new safety signals, and resulted in improved hemoglobin and platelet levels, as well as liver and spleen volumes.
2026-04-20 | Adverse events signals of enzyme replacement drugs of Gaucher disease: insights from FAERS database analysis.
This study aims to investigate and compare the post-marketing safety profiles of three widely used enzyme replacement therapies (ERTs) for Gaucher disease-imiglucerase, velaglucerase alfa, and taliglucerase alfa. ERT involves the intravenous administration of recombinant lysosomal enzymes to compensate for the deficiency of β-glucocerebrosidase, thereby reducing the accumulation of glucocerebroside in macrophages and alleviating systemic complications. While ERT has transformed disease management, concerns about long-term adverse events persist. This analysis seeks to identify and characterize distinct safety signals associated with each agent, with a focus on disproportionality analysis rather than establishing causality. The findings aim to inform more vigilant, agent-specific clinical monitoring. Adverse event reports were extracted from the FDA Adverse Event Reporting System (FAERS) database. Disproportionality analyses were performed using the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS). Patient demographics, significant Preferred Terms (PTs-i.e., specific, medically-encoded adverse event descriptions), and time to onset were examined. A total of 4,256 AE reports were analyzed. Our signal detection analysis identified a distinct set of statistically significant safety signals for each drug after controlling for background reporting rates. These included 37 significantly associated PTs for imiglucerase, 34 for velaglucerase alfa, and 25 for taliglucerase alfa. The safety profiles differed notably; a significant proportion of the signals for imiglucerase and velaglucerase alfa were infection-related (e.g., respiratory tract infections), whereas such signals were far less prominent for taliglucerase alfa. Unique signals included ear infection for imiglucerase, zinc deficiency for velaglucerase alfa, and hepatic fibrosis for taliglucerase alfa. The median time to onset of these signals differed significantly between agents (p < 0.01). Long-term monitoring is essential during ERT for GD. Clinical vigilance should be heightened for infection-related complications with imiglucerase and velaglucerase alfa, while agent-specific risks like hepatic fibrosis with taliglucerase alfa warrant attention. The observed female predominance in AE reports merits further investigation. These findings are hypothesis-generating; future studies are needed to determine causality.
2026-04-16 | Addressing kyphoscoliosis in Gaucher's disease: a multidisciplinary approach to a rare case.
BACKGROUND: Gaucher’s disease (GD) is a rare autosomal recessive disorder caused by mutations in the GBA gene, leading to glucocerebrosidase deficiency and the accumulation of glucosyl ceramide in the bone marrow, which can result in skeletal complications such as scoliosis and kyphosis. Surgical interventions for orthopedic manifestations in GD are challenging and have been rarely reported. STUDY DESIGN: A clinical retrospective study. CASE PRESENTATION: We report an 18-year-old female with Gaucher’s disease who presented with kyphoscoliosis and was treated with a combination of medical and surgical interventions. Preoperatively, she underwent enzyme replacement therapy and cephalic loop traction to correct anemia, coagulation abnormalities, and improve spinal deformity flexibility. She then underwent T12 column resectomy and Smith-Peterson resectomies at T5-10 and L1-3, followed by kyphoscoliosis correction, internal fixation, and fusion surgery. Postoperatively, there was a significant correction of the main coronal curve and kyphosis, with stable outcomes at the 3.5-year follow-up. CONCLUSION: This case represents a rare instance of kyphoscoliosis due to Gaucher’s disease treated with vertebral resection and fusion surgery. The perioperative management, including enzyme replacement therapy and spinal traction, was crucial for the surgical success. This report contributes to the understanding of surgical treatment options for severe spinal deformities in GD and highlights the importance of a multidisciplinary approach. Further studies with longer follow-up periods and additional cases are needed to validate the long-term effectiveness of this technique.
small molecules
2026-09-26 | Miglustat in Neuronopathic Lysosomal Storage Disorders: Biological Rationale, Clinical Evidence, and Limits of Repurposing.
Neuronopathic lysosomal storage disorders remain difficult to treat because conventional enzyme replacement therapies generally do not reach therapeutically meaningful concentrations in the central nervous system. Miglustat (1,5-(butylimino)-1,5-dideoxy-D-glucitol; N-butyl-deoxynojirimycin) is an orally administered iminosugar that crosses the blood-brain barrier and reduces glycosphingolipid synthesis through inhibition of glucosylceramide synthase. This narrative review evaluated the biological rationale, clinical evidence, and limitations of miglustat repurposing across neuronopathic lysosomal storage disorders. PubMed/MEDLINE was searched from inception through 31 July 2026, with backward citation searching. Miglustat has established clinical benefit in Niemann-Pick disease type C, whereas a randomized trial in Gaucher disease type 3 did not demonstrate neurological efficacy. Evidence in GM1 gangliosidosis, Sandhoff disease, mucolipidosis type IV, and CLN3 disease is encouraging but limited to preclinical studies, small uncontrolled series, or individual reports; controlled studies in late-onset Tay-Sachs disease and mucopolysaccharidosis type III were negative. Central nervous system penetration and biochemical target engagement therefore cannot be equated with clinical disease modification. Future repurposing should require disease-specific mechanistic justification, pharmacodynamic biomarkers, natural-history comparators, and intervention before irreversible neurodegeneration.
2026-09-24 | MA-5 attenuates disease-associated transcriptomic aging and pathological microglial states in Gaucher disease.
Chronic inflammation and mitochondrial dysfunction are hallmarks of neurodegeneration and aging, yet how mitochondrial damage contributes to inflammatory and aging-like cellular programs remains poorly understood. Gaucher disease (GD) is a lysosomal storage disorder caused by GBA1 mutations, which also represent a major genetic risk factor for Parkinson's disease. In a GD mouse model, we identified marked mitochondrial cristae disorganization accompanied by mitochondrial DNA release, activation of the cGAS-STING and NLRP3 inflammasome pathways, and subsequent inflammatory microglial activation. Circulating galectin-3 was also elevated in both model mice and patients with GD, supporting its potential relevance as a systemic marker of disease-associated inflammation. Mitochonic acid-5 (MA-5) is a mitochondria-targeting compound that interacts with mitofilin/MIC60 in the mitochondrial inner membrane and enhances ATP production. In a GD mouse model and patient-derived iPSC microglia, MA-5 increased ATP levels, preserved mitochondrial cristae integrity, limited mtDNA release, and suppressed cGAS-STING and NLRP3 inflammasome signaling, thereby attenuating microglial innate immune activation and galectin-3 expression. MA-5 also prolonged survival and reversed accelerated transcriptomic aging across multiple brain cell types, with particularly prominent effects in microglia. In the liver, GD was similarly associated with inflammatory, stress-related, and aging-associated transcriptional changes, whereas MA-5 improved liver function, restored mitochondrial morphology, suppressed inflammatory and stress responses, restored metabolic programs, and reduced transcriptomic age. Overall, MA-5 suppresses neuroinflammation and reverses accelerated transcriptomic aging, supporting its potential as a therapeutic strategy for GD and other lysosomal storage disorders, as well as for diseases characterized by mitochondrial dysfunction, chronic inflammation, and pathological accumulation.
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.
2026-06-18 | Cumulative Antigen Suppression Reduces Clonal Plasma Cell Evolution in Gaucher Disease.
Chronic antigenic stimulation is implicated in the pathogenesis of monoclonal gammopathy and multiple myeloma, yet longitudinal human evidence linking sustained antigen exposure to modifiable clonal plasma cell evolution remains limited. Gaucher disease (GD), caused by biallelic GBA1 pathogenic variants, is characterized by accumulation of glucosylsphingosine (LysoGL1), the direct antigenic target of GD-associated clonal immunoglobulins and a pharmacologically suppressible stimulus. We conducted a longitudinal retrospective cohort study of 235 adults with GD (3628 person-years; 2662 clinical visits), with incident-only ascertainment from a confirmed gammopathy-free baseline. Thirty-one patients (13.2%) developed incident monoclonal gammopathy. GD conferred a ninefold excess risk relative to population expectations (SIR 9.04; 95% CI 5.79-13.45). Male sex independently increased hazard 3.3-fold (HR 3.30; 95% CI 1.55-7.03; p < 0.01), mirroring the established male predominance of plasma cell dyscrasias. GD-specific therapy, initiated solely for systemic disease indications, was associated with a dose-dependent reduction in incident risk. In univariate Cox regression with age as the time scale, each additional therapy year conferred a 9% lower hazard (HR 0.91; 95% CI 0.88-0.94; p < 0.001), extending mean MGUS-free time by 8.4 years between untreated and most-treated quartiles. Cumulative therapy progressively suppressed circulating LysoGL1, with eliglustat achieving substantially deeper reduction than enzyme replacement therapy alone. Propensity score-weighted analyses were directionally concordant (IPTW HR 0.19; 95% CI 0.11-0.30; p < 0.001). These findings establish GD as a tractable model of antigen-driven oncogenesis-and provide a precedent for investigating whether therapeutic reduction of a defined antigenic stimulus can modify oncogenic trajectory in other chronic inflammatory states.
2026-06-17 | persistent pain and fatigue drive reduced quality of life in treated Gaucher disease type 1: a cross-sectional analysis.
Gaucher disease type 1 (GD1) is a multisystem lysosomal disorder in which treatment with enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) improves key clinical parameters. However, many patients continue to experience persistent symptoms that are not captured by traditional disease markers. This study evaluated the relationship between pain, fatigue, and health-related quality of life (HRQoL) among treated adults with GD1. In this cross-sectional study, adults with GD1 receiving ERT or SRT (N = 97) completed an online survey including the 36-item Short Form Survey (SF-36), PROMIS® Fatigue and Pain Interference Short Forms, and the Treatment Satisfaction Questionnaire for Medication©. Associations between demographic factors, treatment variables, symptoms, and HRQoL were assessed using correlation analyses, t-tests, ANOVA, and multiple regression. Pain and fatigue were strong, independent predictors of both physical and mental HRQoL, with age additionally predicting physical HRQoL. Significant negative correlations were observed between pain and HRQoL (physical and mental), as well as between fatigue and HRQoL. Participants reported significantly lower HRQoL compared with U.S. population norms across 7 of 8 SF-36 domains. Persistent pain and fatigue represent major, under-recognized drivers of impaired quality of life in treated GD1, indicating that current therapies do not fully address the symptomatic burden of disease. These findings support routine integration of validated patient-reported outcome measures into clinical care and highlight the need for adjunctive and mechanism-based approaches to improve patient-centered outcomes.
cell therapies
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.
2025-12-30 | Refining Mouse Models of Gaucher Disease: Advancing Mechanistic Insights, Biomarker Discovery, and Therapeutic Strategies.
Gaucher disease (GD), caused by biallelic pathogenic variants in GBA1, has evolved from being understood as a macrophage-restricted lysosomal disorder to a multisystem condition involving neuroinflammation, immune dysregulation, and cell-type-specific lipid toxicity. This expanded view has driven a parallel progression in GD mouse model development. Early chemically induced and germline knockout models provided foundational insights but were limited by perinatal lethality or incomplete phenotypic fidelity. Subsequent generations of conditional, inducible, and lineage-specific models enabled dissection of visceral and neuronopathic manifestations and clarified the contributions of macrophages, B cells, neurons, microglia, osteoblasts, and endothelial cells to disease pathogenesis. More recent humanized immune and gene-edited platforms, together with multi-omics integration, now allow modeling of genotype-specific biology and therapeutic response with greater translational precision. In this review, we synthesize the evolution of GD mouse models across these eras, evaluate their strengths and limitations, and highlight species-specific challenges including differences in lipid metabolism, immune architecture, and the absence of the GBAP1 pseudogene in mice that influence interpretation and clinical translation. We outline emerging strategies for incorporating patient-derived mutations, modifier pathways, and clinically meaningful endpoints into future models. Our aim is to provide a coherent framework that bridges murine and human GD biology and supports the development of more predictive platforms to accelerate mechanistic discovery, biomarker development, and therapeutic innovation across all subtypes of GD.
2025-11-03 | Cytotoxic lymphocyte effector function is unaffected in patients with Gaucher disease.
Gaucher disease (GD) is one of the most common lysosomal storage disorders. It is caused by bi-allelic mutations in the GBA1 gene responsible for the production of β-glucocerebrosidase, an enzyme responsible for the hydrolysis of the sphingolipid glucocerebroside. This results in its accumulation in various organs, and patients can present with a variety of symptoms ranging from visceral enlargement, bone pathology and hematological manifestations. Neuronopathic effects are seen in the severe form of the disease. GD patients also have an increased risk of B-cell malignancies. Some of the hematological symptoms of GD resemble those of the systemic hyperinflammatory condition, hemophagocytic lymphohistiocytosis (HLH). HLH can be familial, due to functional deficiencies in cytotoxic lymphocytes, or acquired from a variety of causes ranging from infections to blood cancers. While patients with inherited and acquired HLH receive the same first-line therapy, patients with the familial form can only be cured by stem cell transplantation, although this treatment may be detrimental to patients with the acquired form of the disease. Therefore, we investigated whether the abnormal lipid accumulation in GD patient cytotoxic lymphocytes and in cells with irreversibly inhibited glucocerebrosidase activity affects their cytotoxicity. Our detailed analysis of primary cytotoxic T lymphocytes and natural killer cells revealed that the activity of these cells was not affected. This finding has important implications for the treatment choices for patients with GD and suggests that these patients can be treated with autologous immunotherapy if they develop hematological cancers.
2025-09-18 | [Application of umbilical cord mesenchymal stem cells in the treatment of severe immune-mediated thrombocytopenia after allogeneic hematopoietic stem cell transplantation in children].
This report describes two cases of severe immune-mediated thrombocytopenia after allogeneic hematopoietic stem cell transplantation (HSCT) who were treated with umbilical cord mesenchymal stem cells (UC-MSCs). Case 1 was a child with severe aplastic anemia who underwent haploidentical bone marrow and peripheral blood HSCT, with a chimerism rate of 99.8% on day +25 and severe immune-mediated thrombocytopenia on day +60. After intravenous immunoglobulin (IVIG) pulse therapy, platelet count increased temporarily but then decreased, while cyclosporine, methylprednisolone, and rituximab had a poor therapeutic effect. Case 2 was a child with Gaucher's disease who underwent unrelated umbilical cord blood HSCT, with a chimerism rate of 96.35% on day +41 and severe immune-mediated thrombocytopenia on day +153. After three sessions of IVIG pulse therapy, the platelet count increased initially but subsequently decreased. Therapies with dexamethasone, prednisone, cyclosporine, and recombinant human thrombopoietin also yielded a poor response. Both children received three sessions of UC-MSCs infusion, and platelet counts increased and were subsequently maintained within the normal range. Case 1 has been followed up for 10 years and remains in disease-free survival. UC-MSCs infusion may be effective for severe immune-mediated thrombocytopenia that is unresponsive to first- and second-line therapies after HSCT and could potentially improve the quality of life and disease-free survival rate.
2025-04-08 | Modeling bone marrow microenvironment and hematopoietic dysregulation in Gaucher disease through VavCre mediated Gba deletion.
Biallelic mutations in Gba cause Gaucher disease (GD), a lysosomal disorder characterized by deficient glucocerebrosidase activity and the accumulation of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph), primarily in macrophages. Beyond macrophages, GD pathology affects additional hematopoietic lineages, contributing to immune dysregulation. Existing Mx1-Cre Gba knockout models require induction protocols that lead to gene deletion outside hematopoietic cells, limiting the study of hematopoietic-specific effects. To overcome these limitations, we generated a hematopoietic-specific Gba knockout model by crossing Gbafl/fl mice with Vav-Cre, enabling early deletion of Gba exons 8-11 in hematopoietic stem and progenitor cells. These mice were backcrossed to 129X1/SvJ and C57BL/6 J backgrounds, revealing that genetic background significantly influences disease severity. Efficient Gba excision was confirmed in bone marrow, spleen, and thymus, with minimal recombination in the liver. In VavCre 129 GD mice, glucocerebrosidase activity in the spleen was severely reduced, leading to GlcCer and GlcSph accumulation and Gaucher cell infiltration in the spleen and femurs. Transcriptomic analysis identified upregulation of inflammatory and lysosomal pathways. Immune cell deconvolution from RNA-seq data further revealed an expansion of monocytes, dendritic cells, and pro-inflammatory macrophage subsets, suggesting an altered immune landscape. Additionally, GPNMB, a potential GD biomarker, was significantly elevated in both spleens and sera of VavCre 129 GD mice. This hematopoietic-specific GD model provides a powerful platform for studying GD pathophysiology, modifier genes, and immune dysregulation. It offers new opportunities for biomarker discovery and for developing strategies targeting hematopoietic and immune mechanisms in GD and related lysosomal storage disorders.
gene therapies
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.
2026-06-23 | Patient-specific midbrain organoids with CRISPR correction recapitulate neuronopathic Gaucher disease phenotypes and enable evaluation of novel therapies.
Neuronopathic Gaucher disease (nGD) is a lysosomal storage disorder caused by GBA1 mutations, leading to defective acid β-glucosidase (GCase) and accumulation of glycosphingolipid substrates, causing inflammation and neurodegeneration. Patients with nGD manifest severe neurological symptoms, but current animal models fail to fully recapitulate the human condition, posing a major barrier to the development of effective therapies targeting the brain. To bridge this gap, we have developed midbrain-like organoids (MLOs) from human induced pluripotent stem cells of nGD patients with GBA1L444P/P415R and GBA1L444P/RecNcil mutations to model nGD brain pathogenesis. These nGD MLOs exhibited GCase deficiency, resulting in diminished enzymatic function, accumulation of lipid substrates, widespread transcriptomic changes, and impaired dopaminergic neuron differentiation, mirroring nGD pathology. GBA1 mutation correction mediated by CRISPR/Cas9 restored GCase activity, normalized lipid substrate levels, and rescued dopaminergic neuron function, confirming the causal role of GBA1 mutations during early brain development. Using this novel platform, we further evaluated therapeutic strategies, including SapC-DOPS nanovesicles delivering GCase, AAV9-GBA1 gene therapy, and substrate reduction therapy with GZ452, a glucosylceramide synthase inhibitor currently under clinical investigation. These treatments either restored GCase activity, reduced lipid substrate accumulation, improved autophagic and lysosomal abnormalities, or ameliorated dysregulated genes involved in neural development. These patient-specific, 3D neural models offer a transformative, physiologically relevant platform for unraveling disease mechanisms and accelerating the discovery of therapies for patients with nGD.
2026-06-22 | Gaucher Disease Treated With Lentiviral-Mediated Gene Therapy: First Case.
Gaucher disease is a rare, autosomal recessive disease, with decreased activity of lysosomal glucocerebrosidase (GCase) due to changes in the GBA1 gene. There is no cure for Gaucher disease, and standard treatment involves the use of enzyme replacement therapy or substrate reduction therapy. We describe the first case of Gaucher disease that was treated with an autologous transplant of lentivirus-transduced CD34+ cells. Enzyme therapy was stopped 4 weeks prior to Day 0 of transplant. At 5 years of follow-up, dried blood spot GCase enzyme levels have remained in the normal range; there has been a consistent and sustained reduction of lyso-GB1 and liver volume, and hematological indices such as leukocyte count, hemoglobin, and platelet count have remained in the normal range despite no additional therapy for the Gaucher disease. This case shows a sustained response to a single dose of lentiviral gene therapy for Gaucher disease.
2026-05-19 | Pharmacotherapies for Gaucher disease: what's new on the horizon?
Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder that results in the accumulation of glucosylceramide (GluCer) within macrophages. Current treatments for GD include enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) to reduce the total amount of GluCer and improve organ function. We review the two main FDA approved therapies for GD, ERT and SRT, including advances in ERT/SRT delivery and new clinical trials using Pubmed and trial databases. New and emerging therapies for GD are discussed in depth, including pre-clinical and clinical studies of small molecule drugs, gene therapy, and nanotechnology. An overview of current clinical trials for GD is provided. Current therapies have vastly improved the health and quality of life for patients. Future efforts in therapeutic development should focus primarily on brain penetrant therapies that will ameliorate neuronopathic GD as well as GBA1-related Parkinson disease. These therapies should be assessed using specific biomarkers that are well validated through advances in translational research.
2026-01-01 | GAUCHER DISEASE: PATHOPHYSIOLOGY, CLINICAL MANIFESTATIONS, DIAGNOSIS AND EMERGING THERAPEUTIC STRATEGIES
Gaucher disease is a lysosomal storage disorder that is rare and has an autosomal recessive inheritance pattern. The disorder is due to the absence (deficiency) of the β-glucocerebrosidase enzyme, resulting in the accumulation of glucocerebroside in macrophages. This accumulation of glucocerebrosides causes multi-systemic manifestations, with the most common organs affected being the liver, spleen, bone marrow, and sometimes the central nervous system. There are three subtypes based on the presence or absence of central nervous system (CNS) involvement: non-neuronopathic (type 1) Gaucher disease and neuronopathic forms (types 2 and 3). Common clinical manifestations include hepatosplenomegaly, anaemia, thrombocytopenia, bony abnormalities, and, in severe forms, neurological complications. The primary means of making a diagnosis is through β-glucocerebrosidase enzyme assay testing and/or GBA1 genetic testing. The treatment currently available is enzyme replacement therapy (ERT) and substrate reduction therapy (SRT), both of which improve systemic manifestations but are limited in their neurologic effect due to the presence of the blood–brain barrier. Other emerging treatment approaches, such as gene therapy, pharmacological chaperones, and nanoparticle-mediated drug delivery, could provide insight into new treatment strategies in the future. The purpose of this review is to provide an overview of the pathophysiology, clinical characteristics, diagnostic methods, and treatment approaches of Gaucher disease.
other
2026-08-19 | RAF/MEK clamp inhibition with avutometinib and cetuximab in RAF1 S257L-mutated, anti-EGFR-refractory metastatic colorectal cancer in Gaucher's disease.
RAF1 alterations are rare in metastatic colorectal cancer (mCRC), occurring in roughly 0.5% of cases, and lack established treatment guidance. We present a patient with RAF1 S257L-mutated, RAS wild-type mCRC and concurrent type 1 Gaucher disease, whose baseline cytopenias precluded standard chemotherapy and clinical-trial enrollment. After progression on fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens (the latter with the anti-EGFR antibody panitumumab) complicated by recurrent neutropenic sepsis, he received off-label avutometinib and defactinib (an oral RAF/MEK clamp inhibitor plus a FAK inhibitor) combined with cetuximab. He achieved a radiographic response, biomarker decline, hematologic recovery, and improvement in ECOG performance status from 3 to 0, with benefit lasting approximately 6 months. At progression, circulating tumor DNA revealed persistence of RAF1 S257L at high allele fraction with RAF1 amplification, together with newly acquired EGFR ectodomain mutations, KRAS alterations, and a MAP2K1 alteration-a polyclonal pattern of convergent MAPK/EGFR reactivation. This case illustrates how a molecular tumor board can translate a rare driver into a rational, individualized regimen and how serial liquid biopsy informs resistance and next steps.
2026-05-04 | A Multiscale Signaling-Biophysical Framework Reveals Mechanisms of Macrophage-Mediated RBC Clearance in Sickle Cell and Gaucher Disease.
Red blood cell (RBC) clearance by macrophages maintains blood homeostasis and is dysregulated in the hemolytic disorder sickle cell disease (SCD) and the lysosomal storage disorder Gaucher disease (GD), where biophysical and biochemical alterations promote premature phagocytosis. We develop a multiscale hybrid modeling framework integrating signaling dynamics, biophysical simulations, and machine learning to investigate the mechanisms governing RBC phagocytosis in these diseases. Our approach couples a systems biology model of macrophage-RBC signaling with Dissipative Particle Dynamics (DPD) simulations of molecular diffusion and membrane interactions, and leverages Physics-Informed Neural Networks (PINNs) for robust parameter inference. The DPD framework provides mechanistic insight into antibody diffusion, receptor engagement, and membrane-level interactions during macrophage-RBC contact, generating spatially resolved trajectories of CD47-SIRPα signaling and antibody-receptor binding that serve as intermediate observables constraining the signaling model. The model accurately captures differential phagocytic responses between healthy and altered RBCs, revealing diminished inhibitory signaling and changes in SHP1-mediated pathways in both SCD and GD. Identifiability analysis combining Fisher Information Matrix diagnostics and profile likelihood confirms that parameters governing the CD47-SIRPα-SHP1 axis are among the most robustly recoverable, and simulations of therapeutic perturbations with anti-SIRPα antibodies demonstrate modulation of engulfment outcomes. We further employ Physics-Informed Kolmogorov-Arnold Networks (PIKANs) as an alternative to standard PINNs, demonstrating improved robustness under noise and sampling variability. More broadly, our multiscale platform linking biophysical simulation with systems-level inference is generalizable, offering mechanistic insights and computational tools for therapeutic exploration in diseases involving dysregulated phagocytosis.
2026-04-24 | Targeted delivery of glucocerebrosidase to lysosomes: The LYSOTAC (LYSOsome-TArgeting Chimera) technology.
Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders caused by misfolding of lysosomal proteins and their degradation via endoplasmic reticulum-associated degradation (ERAD). Deficiency in LSD-associated enzymes leads to the accumulation of toxic materials within the lysosome. In macroautophagy (hereafter autophagy), autophagic receptors as represented by p62/SQSTM1/Sequestosome-1 collect and deliver their cargoes to the lysosome. Here, we developed the LYSOTAC (LYSOsome-TArgeting Chimera) technology, which enables lysosomal targeting of LSD-associated enzymes while preserving their enzymatic activities. LYSOTAC employs a bifunctional chimera that simultaneously binds an LSD-associated enzyme via the enzyme-binding ligand (EBL) and p62 via the autophagy-targeting ligand (ATL). Upon binding, p62 undergoes self-polymerization to form cargo-p62 complexes, which are sequestered into autophagosomes and delivered to lysosomes, where the enzymes exhibit maximal activity. Here, LYSOTAC compounds targeting β-glucocerebrosidase (GCase) were designed to restore GCase activity in lysosomes and promote glucosylceramide degradation in Gaucher disease fibroblasts. We suggest that LYSOTAC provides a potential therapeutic strategy for LSDs.
2026-02-21 | Structural analysis of the plant glycoside hydrolase family 116 glucosylceramidase AtGCD3 by cryogenic electron microscopy.
Glucosylceramide (GlcCer) is a common glycosphingolipid that accumulates in cells in response to Gaucher disease, diabetes, and skin disorders in humans and is also found in plants. In animals, GlcCer is catabolized by glucosylcerebrosidase 1 and 2 (GBA1 and GBA2). GBA1 is a lysosomal enzyme in glycoside hydrolase (GH) family GH30, while GBA2 is a membrane-associated cytoplasmic protein in family GH116. Currently, there are no experimental structures of eukaryotic GH116 homologues. Although the bacterial TxGH116 β-glucosidase structure was determined by X-ray crystallography, TxGH116 does not hydrolyze glucosylceramides, unlike the animal and plant enzymes. Therefore, we have investigated the structure of plant GH116 (AtGCD3) by cryogenic electron microscopy (Cryo-EM) single-particle analysis. The recombinant AtGCD3 protein was produced in Escherichia coli and purified by immobilized-metal affinity chromatography followed by size-exclusion chromatography. The Cryo-EM structure revealed a unique hexameric arrangement, composed of a dimer of trimers. Hydrophobic interactions and hydrogen bonds stabilize each trimer at the trimer interface. The two trimers stack face-to-face with a slight twist, with salt bridges and hydrogen bonding at their interface. Two α-helices not found in previously described GH116 structures cover the active site, forming two hydrophobic channels that may be involved in glucosylceramide binding. Molecular dynamics simulations showed that glucosylceramide can bind stably in the active site with its lipid tails in these channels. This first eukaryotic structure of a GH116 enzyme generates a template for improved modeling of human GBA2, with implications for treating human diseases, such as Gaucher disease and hereditary spastic paraplegia.
2025-06-14 | A Randomized, Double-Blind, 2-Treatment, 2-Period, Crossover Phase 1 Study to Compare the Pharmacokinetics, Safety and Tolerability of 60 IU/Kg of Abcertin and Cerezyme in Healthy Volunteers Following a Single Intravenous Administration.
Imiglucerase (Cerezyme; Sanofi, Paris, France), an analogue of β-glucocerebrosidase produced by recombinant DNA technology, has been a safe and effective treatment for Gaucher disease (GD) for over 25 years. A new imiglucerase, Abcertin (Seongnam-si, Gyeonggi-do, Republic of Korea) has shown a similar safety and efficacy profile in previous clinical studies. This study compared the pharmacokinetics, immunogenicity, safety, and tolerability to EU-sourced Cerezyme following a single 60 IU/kg dose. This phase 1, single-center, randomized, double-blind, two-way crossover study enrolled 36 healthy volunteers aged 18-45 years. Participants were randomly assigned to receive either Abcertin or Cerezyme in a predetermined sequence. Abcertin reached peak plasma concentrations at a median tmax of 61 min (range: 40-121 min). The mean Cmax, AUC0-last, and AUC0-inf were 115.4 mU/mL, 12,190 min·mU/mL, and 12,210 min mU/mL, respectively, indicating bioequivalence to Cerezyme. The mean t½, CL, and Vz were 6.88 min, 376.7 mL/min, and 3.62 L, respectively, and were comparable between the two treatments. One participant in the Cerezyme group developed anti-drug antibodies, which were non-neutralizing A total of 24 subjects experienced treatment-emergent adverse event (TEAE). The most common TEAE was headache (3 in the Abcertin group and 5 in the Cerezyme group), followed by general disorders and administration site condition (3 in Abcertin group and 5 in Cerezyme group). Two participants in the Cerezyme sequence experienced severe TEAEs: one had a urinary tract infection, and the other developed urticaria, which leading to study withdrawal. Abcertin demonstrated pharmacokinetic equivalence to Cerezyme, with a comparable safety, immunogenicity, and tolerability profile. These findings support its potential as an affordable biosimilar for GD treatment.
proteins
2026-08-31 | Conserved water molecules shape the pathogenicity of missense variants in human proteins.
Conserved water molecules (CWMs) are tightly bound solvent molecules that occupy well-defined, recurrent positions in protein structures. Although they are known to influence protein stability, function, and ligand binding, their role in shaping the effects of human missense variants remains largely unexplored. Here, we demonstrate that CWMs are a previously underappreciated determinant of missense variant pathogenicity. By predicting ligand-binding and CWM sites across human PDB structures and mapping missense variants to these sites and the remaining protein surface, we found that pathogenic variants were significantly enriched at CWM sites, whether overlapping or outside other ligand-binding regions. This enrichment exceeded that observed for binding sites as a whole, indicating a broader role for water-mediated interactions in modulating variant effects. To explore a mechanistic basis for this association, we performed molecular dynamics simulations of human lysosomal acid glucosylceramidase (GCase), encoded by GBA1 and implicated in Gaucher disease and Parkinson's disease risk. Selective destabilization of a CWM site in wild-type GCase produced structural and dynamical changes resembling those observed in the pathogenic L444P variant, whereas stabilization of this site in L444P shifted several measures toward wild-type behavior. These results suggest that disruption of a single CWM can contribute to long-range structural remodeling observed in a disease-associated variant. Together, our findings identify CWMs as a novel structural constraint shaping the distribution and effects of pathogenic missense variants. Incorporating water-mediated interactions into structural models provides a generalizable framework for interpreting human genetic variation and its contribution to disease.
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.
2026-06-15 | A 53-week, open-label phase IIIb study of velaglucerase alfa in Chinese patients with type 1 Gaucher disease: Safety, efficacy, and pharmacokinetics.
Velaglucerase alfa is approved in China for treating type 1 Gaucher disease (GD1), but data on its use in Chinese pediatric and adult patients are limited. This study evaluated the safety, efficacy, and pharmacokinetics of velaglucerase alfa in Chinese patients with GD1. This was a phase IIIb, multicenter, open-label, single-arm, 53-week study (NCT05529992). Patients received intravenous velaglucerase alfa (60 U/kg) every 2 weeks. The primary endpoint was the incidence of serious treatment-emergent adverse events (TEAEs). Secondary endpoints evaluated safety (incidence of TEAEs), efficacy (changes in hemoglobin concentrations, platelet counts, liver and spleen volumes [as percent of body weight, % BW]), and quality of life (QoL). Twenty patients were enrolled (treatment-naïve, n = 16; previously treated, n = 4). Four patients experienced 4 serious TEAEs requiring hospitalization; none were treatment-related. Overall, 19 of 20 patients experienced 104 TEAEs, of which 9 were treatment-related (8.7%; all mild). No TEAEs or deaths led to discontinuation of treatment. Mean (SD) improvements in hemoglobin concentrations (baseline, 10.5 g/dL [2.2]; change, +2.3 g/dL [1.3]; +25.5%), platelet counts (baseline, 59.9 × 109/L [23.4]; change, +42.1 × 109/L [27.7]; +82.3%), normalized spleen (baseline, 5.2% BW [2.6]; change, -3.1% BW [1.6]; -58.4%), and liver volume (baseline, 4.6% BW [1.3]; change, -1.1% BW [0.9]; -21.5%) were observed through Week 53. Nineteen of 20 (95.0%) patients reported improved QoL. Velaglucerase alfa was well-tolerated in Chinese patients with GD1, with no new safety signals, and resulted in improved hemoglobin and platelet levels, as well as liver and spleen volumes.
2026-04-20 | Adverse events signals of enzyme replacement drugs of Gaucher disease: insights from FAERS database analysis.
This study aims to investigate and compare the post-marketing safety profiles of three widely used enzyme replacement therapies (ERTs) for Gaucher disease-imiglucerase, velaglucerase alfa, and taliglucerase alfa. ERT involves the intravenous administration of recombinant lysosomal enzymes to compensate for the deficiency of β-glucocerebrosidase, thereby reducing the accumulation of glucocerebroside in macrophages and alleviating systemic complications. While ERT has transformed disease management, concerns about long-term adverse events persist. This analysis seeks to identify and characterize distinct safety signals associated with each agent, with a focus on disproportionality analysis rather than establishing causality. The findings aim to inform more vigilant, agent-specific clinical monitoring. Adverse event reports were extracted from the FDA Adverse Event Reporting System (FAERS) database. Disproportionality analyses were performed using the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS). Patient demographics, significant Preferred Terms (PTs-i.e., specific, medically-encoded adverse event descriptions), and time to onset were examined. A total of 4,256 AE reports were analyzed. Our signal detection analysis identified a distinct set of statistically significant safety signals for each drug after controlling for background reporting rates. These included 37 significantly associated PTs for imiglucerase, 34 for velaglucerase alfa, and 25 for taliglucerase alfa. The safety profiles differed notably; a significant proportion of the signals for imiglucerase and velaglucerase alfa were infection-related (e.g., respiratory tract infections), whereas such signals were far less prominent for taliglucerase alfa. Unique signals included ear infection for imiglucerase, zinc deficiency for velaglucerase alfa, and hepatic fibrosis for taliglucerase alfa. The median time to onset of these signals differed significantly between agents (p < 0.01). Long-term monitoring is essential during ERT for GD. Clinical vigilance should be heightened for infection-related complications with imiglucerase and velaglucerase alfa, while agent-specific risks like hepatic fibrosis with taliglucerase alfa warrant attention. The observed female predominance in AE reports merits further investigation. These findings are hypothesis-generating; future studies are needed to determine causality.
2026-04-16 | Addressing kyphoscoliosis in Gaucher's disease: a multidisciplinary approach to a rare case.
BACKGROUND: Gaucher’s disease (GD) is a rare autosomal recessive disorder caused by mutations in the GBA gene, leading to glucocerebrosidase deficiency and the accumulation of glucosyl ceramide in the bone marrow, which can result in skeletal complications such as scoliosis and kyphosis. Surgical interventions for orthopedic manifestations in GD are challenging and have been rarely reported. STUDY DESIGN: A clinical retrospective study. CASE PRESENTATION: We report an 18-year-old female with Gaucher’s disease who presented with kyphoscoliosis and was treated with a combination of medical and surgical interventions. Preoperatively, she underwent enzyme replacement therapy and cephalic loop traction to correct anemia, coagulation abnormalities, and improve spinal deformity flexibility. She then underwent T12 column resectomy and Smith-Peterson resectomies at T5-10 and L1-3, followed by kyphoscoliosis correction, internal fixation, and fusion surgery. Postoperatively, there was a significant correction of the main coronal curve and kyphosis, with stable outcomes at the 3.5-year follow-up. CONCLUSION: This case represents a rare instance of kyphoscoliosis due to Gaucher’s disease treated with vertebral resection and fusion surgery. The perioperative management, including enzyme replacement therapy and spinal traction, was crucial for the surgical success. This report contributes to the understanding of surgical treatment options for severe spinal deformities in GD and highlights the importance of a multidisciplinary approach. Further studies with longer follow-up periods and additional cases are needed to validate the long-term effectiveness of this technique.
small molecules
2026-09-26 | Miglustat in Neuronopathic Lysosomal Storage Disorders: Biological Rationale, Clinical Evidence, and Limits of Repurposing.
Neuronopathic lysosomal storage disorders remain difficult to treat because conventional enzyme replacement therapies generally do not reach therapeutically meaningful concentrations in the central nervous system. Miglustat (1,5-(butylimino)-1,5-dideoxy-D-glucitol; N-butyl-deoxynojirimycin) is an orally administered iminosugar that crosses the blood-brain barrier and reduces glycosphingolipid synthesis through inhibition of glucosylceramide synthase. This narrative review evaluated the biological rationale, clinical evidence, and limitations of miglustat repurposing across neuronopathic lysosomal storage disorders. PubMed/MEDLINE was searched from inception through 31 July 2026, with backward citation searching. Miglustat has established clinical benefit in Niemann-Pick disease type C, whereas a randomized trial in Gaucher disease type 3 did not demonstrate neurological efficacy. Evidence in GM1 gangliosidosis, Sandhoff disease, mucolipidosis type IV, and CLN3 disease is encouraging but limited to preclinical studies, small uncontrolled series, or individual reports; controlled studies in late-onset Tay-Sachs disease and mucopolysaccharidosis type III were negative. Central nervous system penetration and biochemical target engagement therefore cannot be equated with clinical disease modification. Future repurposing should require disease-specific mechanistic justification, pharmacodynamic biomarkers, natural-history comparators, and intervention before irreversible neurodegeneration.
2026-09-24 | MA-5 attenuates disease-associated transcriptomic aging and pathological microglial states in Gaucher disease.
Chronic inflammation and mitochondrial dysfunction are hallmarks of neurodegeneration and aging, yet how mitochondrial damage contributes to inflammatory and aging-like cellular programs remains poorly understood. Gaucher disease (GD) is a lysosomal storage disorder caused by GBA1 mutations, which also represent a major genetic risk factor for Parkinson's disease. In a GD mouse model, we identified marked mitochondrial cristae disorganization accompanied by mitochondrial DNA release, activation of the cGAS-STING and NLRP3 inflammasome pathways, and subsequent inflammatory microglial activation. Circulating galectin-3 was also elevated in both model mice and patients with GD, supporting its potential relevance as a systemic marker of disease-associated inflammation. Mitochonic acid-5 (MA-5) is a mitochondria-targeting compound that interacts with mitofilin/MIC60 in the mitochondrial inner membrane and enhances ATP production. In a GD mouse model and patient-derived iPSC microglia, MA-5 increased ATP levels, preserved mitochondrial cristae integrity, limited mtDNA release, and suppressed cGAS-STING and NLRP3 inflammasome signaling, thereby attenuating microglial innate immune activation and galectin-3 expression. MA-5 also prolonged survival and reversed accelerated transcriptomic aging across multiple brain cell types, with particularly prominent effects in microglia. In the liver, GD was similarly associated with inflammatory, stress-related, and aging-associated transcriptional changes, whereas MA-5 improved liver function, restored mitochondrial morphology, suppressed inflammatory and stress responses, restored metabolic programs, and reduced transcriptomic age. Overall, MA-5 suppresses neuroinflammation and reverses accelerated transcriptomic aging, supporting its potential as a therapeutic strategy for GD and other lysosomal storage disorders, as well as for diseases characterized by mitochondrial dysfunction, chronic inflammation, and pathological accumulation.
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.
2026-06-18 | Cumulative Antigen Suppression Reduces Clonal Plasma Cell Evolution in Gaucher Disease.
Chronic antigenic stimulation is implicated in the pathogenesis of monoclonal gammopathy and multiple myeloma, yet longitudinal human evidence linking sustained antigen exposure to modifiable clonal plasma cell evolution remains limited. Gaucher disease (GD), caused by biallelic GBA1 pathogenic variants, is characterized by accumulation of glucosylsphingosine (LysoGL1), the direct antigenic target of GD-associated clonal immunoglobulins and a pharmacologically suppressible stimulus. We conducted a longitudinal retrospective cohort study of 235 adults with GD (3628 person-years; 2662 clinical visits), with incident-only ascertainment from a confirmed gammopathy-free baseline. Thirty-one patients (13.2%) developed incident monoclonal gammopathy. GD conferred a ninefold excess risk relative to population expectations (SIR 9.04; 95% CI 5.79-13.45). Male sex independently increased hazard 3.3-fold (HR 3.30; 95% CI 1.55-7.03; p < 0.01), mirroring the established male predominance of plasma cell dyscrasias. GD-specific therapy, initiated solely for systemic disease indications, was associated with a dose-dependent reduction in incident risk. In univariate Cox regression with age as the time scale, each additional therapy year conferred a 9% lower hazard (HR 0.91; 95% CI 0.88-0.94; p < 0.001), extending mean MGUS-free time by 8.4 years between untreated and most-treated quartiles. Cumulative therapy progressively suppressed circulating LysoGL1, with eliglustat achieving substantially deeper reduction than enzyme replacement therapy alone. Propensity score-weighted analyses were directionally concordant (IPTW HR 0.19; 95% CI 0.11-0.30; p < 0.001). These findings establish GD as a tractable model of antigen-driven oncogenesis-and provide a precedent for investigating whether therapeutic reduction of a defined antigenic stimulus can modify oncogenic trajectory in other chronic inflammatory states.
2026-06-17 | persistent pain and fatigue drive reduced quality of life in treated Gaucher disease type 1: a cross-sectional analysis.
Gaucher disease type 1 (GD1) is a multisystem lysosomal disorder in which treatment with enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) improves key clinical parameters. However, many patients continue to experience persistent symptoms that are not captured by traditional disease markers. This study evaluated the relationship between pain, fatigue, and health-related quality of life (HRQoL) among treated adults with GD1. In this cross-sectional study, adults with GD1 receiving ERT or SRT (N = 97) completed an online survey including the 36-item Short Form Survey (SF-36), PROMIS® Fatigue and Pain Interference Short Forms, and the Treatment Satisfaction Questionnaire for Medication©. Associations between demographic factors, treatment variables, symptoms, and HRQoL were assessed using correlation analyses, t-tests, ANOVA, and multiple regression. Pain and fatigue were strong, independent predictors of both physical and mental HRQoL, with age additionally predicting physical HRQoL. Significant negative correlations were observed between pain and HRQoL (physical and mental), as well as between fatigue and HRQoL. Participants reported significantly lower HRQoL compared with U.S. population norms across 7 of 8 SF-36 domains. Persistent pain and fatigue represent major, under-recognized drivers of impaired quality of life in treated GD1, indicating that current therapies do not fully address the symptomatic burden of disease. These findings support routine integration of validated patient-reported outcome measures into clinical care and highlight the need for adjunctive and mechanism-based approaches to improve patient-centered outcomes.
cell therapies
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.
2025-12-30 | Refining Mouse Models of Gaucher Disease: Advancing Mechanistic Insights, Biomarker Discovery, and Therapeutic Strategies.
Gaucher disease (GD), caused by biallelic pathogenic variants in GBA1, has evolved from being understood as a macrophage-restricted lysosomal disorder to a multisystem condition involving neuroinflammation, immune dysregulation, and cell-type-specific lipid toxicity. This expanded view has driven a parallel progression in GD mouse model development. Early chemically induced and germline knockout models provided foundational insights but were limited by perinatal lethality or incomplete phenotypic fidelity. Subsequent generations of conditional, inducible, and lineage-specific models enabled dissection of visceral and neuronopathic manifestations and clarified the contributions of macrophages, B cells, neurons, microglia, osteoblasts, and endothelial cells to disease pathogenesis. More recent humanized immune and gene-edited platforms, together with multi-omics integration, now allow modeling of genotype-specific biology and therapeutic response with greater translational precision. In this review, we synthesize the evolution of GD mouse models across these eras, evaluate their strengths and limitations, and highlight species-specific challenges including differences in lipid metabolism, immune architecture, and the absence of the GBAP1 pseudogene in mice that influence interpretation and clinical translation. We outline emerging strategies for incorporating patient-derived mutations, modifier pathways, and clinically meaningful endpoints into future models. Our aim is to provide a coherent framework that bridges murine and human GD biology and supports the development of more predictive platforms to accelerate mechanistic discovery, biomarker development, and therapeutic innovation across all subtypes of GD.
2025-11-03 | Cytotoxic lymphocyte effector function is unaffected in patients with Gaucher disease.
Gaucher disease (GD) is one of the most common lysosomal storage disorders. It is caused by bi-allelic mutations in the GBA1 gene responsible for the production of β-glucocerebrosidase, an enzyme responsible for the hydrolysis of the sphingolipid glucocerebroside. This results in its accumulation in various organs, and patients can present with a variety of symptoms ranging from visceral enlargement, bone pathology and hematological manifestations. Neuronopathic effects are seen in the severe form of the disease. GD patients also have an increased risk of B-cell malignancies. Some of the hematological symptoms of GD resemble those of the systemic hyperinflammatory condition, hemophagocytic lymphohistiocytosis (HLH). HLH can be familial, due to functional deficiencies in cytotoxic lymphocytes, or acquired from a variety of causes ranging from infections to blood cancers. While patients with inherited and acquired HLH receive the same first-line therapy, patients with the familial form can only be cured by stem cell transplantation, although this treatment may be detrimental to patients with the acquired form of the disease. Therefore, we investigated whether the abnormal lipid accumulation in GD patient cytotoxic lymphocytes and in cells with irreversibly inhibited glucocerebrosidase activity affects their cytotoxicity. Our detailed analysis of primary cytotoxic T lymphocytes and natural killer cells revealed that the activity of these cells was not affected. This finding has important implications for the treatment choices for patients with GD and suggests that these patients can be treated with autologous immunotherapy if they develop hematological cancers.
2025-09-18 | [Application of umbilical cord mesenchymal stem cells in the treatment of severe immune-mediated thrombocytopenia after allogeneic hematopoietic stem cell transplantation in children].
This report describes two cases of severe immune-mediated thrombocytopenia after allogeneic hematopoietic stem cell transplantation (HSCT) who were treated with umbilical cord mesenchymal stem cells (UC-MSCs). Case 1 was a child with severe aplastic anemia who underwent haploidentical bone marrow and peripheral blood HSCT, with a chimerism rate of 99.8% on day +25 and severe immune-mediated thrombocytopenia on day +60. After intravenous immunoglobulin (IVIG) pulse therapy, platelet count increased temporarily but then decreased, while cyclosporine, methylprednisolone, and rituximab had a poor therapeutic effect. Case 2 was a child with Gaucher's disease who underwent unrelated umbilical cord blood HSCT, with a chimerism rate of 96.35% on day +41 and severe immune-mediated thrombocytopenia on day +153. After three sessions of IVIG pulse therapy, the platelet count increased initially but subsequently decreased. Therapies with dexamethasone, prednisone, cyclosporine, and recombinant human thrombopoietin also yielded a poor response. Both children received three sessions of UC-MSCs infusion, and platelet counts increased and were subsequently maintained within the normal range. Case 1 has been followed up for 10 years and remains in disease-free survival. UC-MSCs infusion may be effective for severe immune-mediated thrombocytopenia that is unresponsive to first- and second-line therapies after HSCT and could potentially improve the quality of life and disease-free survival rate.
2025-04-08 | Modeling bone marrow microenvironment and hematopoietic dysregulation in Gaucher disease through VavCre mediated Gba deletion.
Biallelic mutations in Gba cause Gaucher disease (GD), a lysosomal disorder characterized by deficient glucocerebrosidase activity and the accumulation of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph), primarily in macrophages. Beyond macrophages, GD pathology affects additional hematopoietic lineages, contributing to immune dysregulation. Existing Mx1-Cre Gba knockout models require induction protocols that lead to gene deletion outside hematopoietic cells, limiting the study of hematopoietic-specific effects. To overcome these limitations, we generated a hematopoietic-specific Gba knockout model by crossing Gbafl/fl mice with Vav-Cre, enabling early deletion of Gba exons 8-11 in hematopoietic stem and progenitor cells. These mice were backcrossed to 129X1/SvJ and C57BL/6 J backgrounds, revealing that genetic background significantly influences disease severity. Efficient Gba excision was confirmed in bone marrow, spleen, and thymus, with minimal recombination in the liver. In VavCre 129 GD mice, glucocerebrosidase activity in the spleen was severely reduced, leading to GlcCer and GlcSph accumulation and Gaucher cell infiltration in the spleen and femurs. Transcriptomic analysis identified upregulation of inflammatory and lysosomal pathways. Immune cell deconvolution from RNA-seq data further revealed an expansion of monocytes, dendritic cells, and pro-inflammatory macrophage subsets, suggesting an altered immune landscape. Additionally, GPNMB, a potential GD biomarker, was significantly elevated in both spleens and sera of VavCre 129 GD mice. This hematopoietic-specific GD model provides a powerful platform for studying GD pathophysiology, modifier genes, and immune dysregulation. It offers new opportunities for biomarker discovery and for developing strategies targeting hematopoietic and immune mechanisms in GD and related lysosomal storage disorders.
gene therapies
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.
2026-06-23 | Patient-specific midbrain organoids with CRISPR correction recapitulate neuronopathic Gaucher disease phenotypes and enable evaluation of novel therapies.
Neuronopathic Gaucher disease (nGD) is a lysosomal storage disorder caused by GBA1 mutations, leading to defective acid β-glucosidase (GCase) and accumulation of glycosphingolipid substrates, causing inflammation and neurodegeneration. Patients with nGD manifest severe neurological symptoms, but current animal models fail to fully recapitulate the human condition, posing a major barrier to the development of effective therapies targeting the brain. To bridge this gap, we have developed midbrain-like organoids (MLOs) from human induced pluripotent stem cells of nGD patients with GBA1L444P/P415R and GBA1L444P/RecNcil mutations to model nGD brain pathogenesis. These nGD MLOs exhibited GCase deficiency, resulting in diminished enzymatic function, accumulation of lipid substrates, widespread transcriptomic changes, and impaired dopaminergic neuron differentiation, mirroring nGD pathology. GBA1 mutation correction mediated by CRISPR/Cas9 restored GCase activity, normalized lipid substrate levels, and rescued dopaminergic neuron function, confirming the causal role of GBA1 mutations during early brain development. Using this novel platform, we further evaluated therapeutic strategies, including SapC-DOPS nanovesicles delivering GCase, AAV9-GBA1 gene therapy, and substrate reduction therapy with GZ452, a glucosylceramide synthase inhibitor currently under clinical investigation. These treatments either restored GCase activity, reduced lipid substrate accumulation, improved autophagic and lysosomal abnormalities, or ameliorated dysregulated genes involved in neural development. These patient-specific, 3D neural models offer a transformative, physiologically relevant platform for unraveling disease mechanisms and accelerating the discovery of therapies for patients with nGD.
2026-06-22 | Gaucher Disease Treated With Lentiviral-Mediated Gene Therapy: First Case.
Gaucher disease is a rare, autosomal recessive disease, with decreased activity of lysosomal glucocerebrosidase (GCase) due to changes in the GBA1 gene. There is no cure for Gaucher disease, and standard treatment involves the use of enzyme replacement therapy or substrate reduction therapy. We describe the first case of Gaucher disease that was treated with an autologous transplant of lentivirus-transduced CD34+ cells. Enzyme therapy was stopped 4 weeks prior to Day 0 of transplant. At 5 years of follow-up, dried blood spot GCase enzyme levels have remained in the normal range; there has been a consistent and sustained reduction of lyso-GB1 and liver volume, and hematological indices such as leukocyte count, hemoglobin, and platelet count have remained in the normal range despite no additional therapy for the Gaucher disease. This case shows a sustained response to a single dose of lentiviral gene therapy for Gaucher disease.
2026-05-19 | Pharmacotherapies for Gaucher disease: what's new on the horizon?
Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder that results in the accumulation of glucosylceramide (GluCer) within macrophages. Current treatments for GD include enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) to reduce the total amount of GluCer and improve organ function. We review the two main FDA approved therapies for GD, ERT and SRT, including advances in ERT/SRT delivery and new clinical trials using Pubmed and trial databases. New and emerging therapies for GD are discussed in depth, including pre-clinical and clinical studies of small molecule drugs, gene therapy, and nanotechnology. An overview of current clinical trials for GD is provided. Current therapies have vastly improved the health and quality of life for patients. Future efforts in therapeutic development should focus primarily on brain penetrant therapies that will ameliorate neuronopathic GD as well as GBA1-related Parkinson disease. These therapies should be assessed using specific biomarkers that are well validated through advances in translational research.
2026-01-01 | GAUCHER DISEASE: PATHOPHYSIOLOGY, CLINICAL MANIFESTATIONS, DIAGNOSIS AND EMERGING THERAPEUTIC STRATEGIES
Gaucher disease is a lysosomal storage disorder that is rare and has an autosomal recessive inheritance pattern. The disorder is due to the absence (deficiency) of the β-glucocerebrosidase enzyme, resulting in the accumulation of glucocerebroside in macrophages. This accumulation of glucocerebrosides causes multi-systemic manifestations, with the most common organs affected being the liver, spleen, bone marrow, and sometimes the central nervous system. There are three subtypes based on the presence or absence of central nervous system (CNS) involvement: non-neuronopathic (type 1) Gaucher disease and neuronopathic forms (types 2 and 3). Common clinical manifestations include hepatosplenomegaly, anaemia, thrombocytopenia, bony abnormalities, and, in severe forms, neurological complications. The primary means of making a diagnosis is through β-glucocerebrosidase enzyme assay testing and/or GBA1 genetic testing. The treatment currently available is enzyme replacement therapy (ERT) and substrate reduction therapy (SRT), both of which improve systemic manifestations but are limited in their neurologic effect due to the presence of the blood–brain barrier. Other emerging treatment approaches, such as gene therapy, pharmacological chaperones, and nanoparticle-mediated drug delivery, could provide insight into new treatment strategies in the future. The purpose of this review is to provide an overview of the pathophysiology, clinical characteristics, diagnostic methods, and treatment approaches of Gaucher disease.
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2026-08-19 | RAF/MEK clamp inhibition with avutometinib and cetuximab in RAF1 S257L-mutated, anti-EGFR-refractory metastatic colorectal cancer in Gaucher's disease.
RAF1 alterations are rare in metastatic colorectal cancer (mCRC), occurring in roughly 0.5% of cases, and lack established treatment guidance. We present a patient with RAF1 S257L-mutated, RAS wild-type mCRC and concurrent type 1 Gaucher disease, whose baseline cytopenias precluded standard chemotherapy and clinical-trial enrollment. After progression on fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens (the latter with the anti-EGFR antibody panitumumab) complicated by recurrent neutropenic sepsis, he received off-label avutometinib and defactinib (an oral RAF/MEK clamp inhibitor plus a FAK inhibitor) combined with cetuximab. He achieved a radiographic response, biomarker decline, hematologic recovery, and improvement in ECOG performance status from 3 to 0, with benefit lasting approximately 6 months. At progression, circulating tumor DNA revealed persistence of RAF1 S257L at high allele fraction with RAF1 amplification, together with newly acquired EGFR ectodomain mutations, KRAS alterations, and a MAP2K1 alteration-a polyclonal pattern of convergent MAPK/EGFR reactivation. This case illustrates how a molecular tumor board can translate a rare driver into a rational, individualized regimen and how serial liquid biopsy informs resistance and next steps.
2026-05-04 | A Multiscale Signaling-Biophysical Framework Reveals Mechanisms of Macrophage-Mediated RBC Clearance in Sickle Cell and Gaucher Disease.
Red blood cell (RBC) clearance by macrophages maintains blood homeostasis and is dysregulated in the hemolytic disorder sickle cell disease (SCD) and the lysosomal storage disorder Gaucher disease (GD), where biophysical and biochemical alterations promote premature phagocytosis. We develop a multiscale hybrid modeling framework integrating signaling dynamics, biophysical simulations, and machine learning to investigate the mechanisms governing RBC phagocytosis in these diseases. Our approach couples a systems biology model of macrophage-RBC signaling with Dissipative Particle Dynamics (DPD) simulations of molecular diffusion and membrane interactions, and leverages Physics-Informed Neural Networks (PINNs) for robust parameter inference. The DPD framework provides mechanistic insight into antibody diffusion, receptor engagement, and membrane-level interactions during macrophage-RBC contact, generating spatially resolved trajectories of CD47-SIRPα signaling and antibody-receptor binding that serve as intermediate observables constraining the signaling model. The model accurately captures differential phagocytic responses between healthy and altered RBCs, revealing diminished inhibitory signaling and changes in SHP1-mediated pathways in both SCD and GD. Identifiability analysis combining Fisher Information Matrix diagnostics and profile likelihood confirms that parameters governing the CD47-SIRPα-SHP1 axis are among the most robustly recoverable, and simulations of therapeutic perturbations with anti-SIRPα antibodies demonstrate modulation of engulfment outcomes. We further employ Physics-Informed Kolmogorov-Arnold Networks (PIKANs) as an alternative to standard PINNs, demonstrating improved robustness under noise and sampling variability. More broadly, our multiscale platform linking biophysical simulation with systems-level inference is generalizable, offering mechanistic insights and computational tools for therapeutic exploration in diseases involving dysregulated phagocytosis.
2026-04-24 | Targeted delivery of glucocerebrosidase to lysosomes: The LYSOTAC (LYSOsome-TArgeting Chimera) technology.
Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders caused by misfolding of lysosomal proteins and their degradation via endoplasmic reticulum-associated degradation (ERAD). Deficiency in LSD-associated enzymes leads to the accumulation of toxic materials within the lysosome. In macroautophagy (hereafter autophagy), autophagic receptors as represented by p62/SQSTM1/Sequestosome-1 collect and deliver their cargoes to the lysosome. Here, we developed the LYSOTAC (LYSOsome-TArgeting Chimera) technology, which enables lysosomal targeting of LSD-associated enzymes while preserving their enzymatic activities. LYSOTAC employs a bifunctional chimera that simultaneously binds an LSD-associated enzyme via the enzyme-binding ligand (EBL) and p62 via the autophagy-targeting ligand (ATL). Upon binding, p62 undergoes self-polymerization to form cargo-p62 complexes, which are sequestered into autophagosomes and delivered to lysosomes, where the enzymes exhibit maximal activity. Here, LYSOTAC compounds targeting β-glucocerebrosidase (GCase) were designed to restore GCase activity in lysosomes and promote glucosylceramide degradation in Gaucher disease fibroblasts. We suggest that LYSOTAC provides a potential therapeutic strategy for LSDs.
2026-02-21 | Structural analysis of the plant glycoside hydrolase family 116 glucosylceramidase AtGCD3 by cryogenic electron microscopy.
Glucosylceramide (GlcCer) is a common glycosphingolipid that accumulates in cells in response to Gaucher disease, diabetes, and skin disorders in humans and is also found in plants. In animals, GlcCer is catabolized by glucosylcerebrosidase 1 and 2 (GBA1 and GBA2). GBA1 is a lysosomal enzyme in glycoside hydrolase (GH) family GH30, while GBA2 is a membrane-associated cytoplasmic protein in family GH116. Currently, there are no experimental structures of eukaryotic GH116 homologues. Although the bacterial TxGH116 β-glucosidase structure was determined by X-ray crystallography, TxGH116 does not hydrolyze glucosylceramides, unlike the animal and plant enzymes. Therefore, we have investigated the structure of plant GH116 (AtGCD3) by cryogenic electron microscopy (Cryo-EM) single-particle analysis. The recombinant AtGCD3 protein was produced in Escherichia coli and purified by immobilized-metal affinity chromatography followed by size-exclusion chromatography. The Cryo-EM structure revealed a unique hexameric arrangement, composed of a dimer of trimers. Hydrophobic interactions and hydrogen bonds stabilize each trimer at the trimer interface. The two trimers stack face-to-face with a slight twist, with salt bridges and hydrogen bonding at their interface. Two α-helices not found in previously described GH116 structures cover the active site, forming two hydrophobic channels that may be involved in glucosylceramide binding. Molecular dynamics simulations showed that glucosylceramide can bind stably in the active site with its lipid tails in these channels. This first eukaryotic structure of a GH116 enzyme generates a template for improved modeling of human GBA2, with implications for treating human diseases, such as Gaucher disease and hereditary spastic paraplegia.
2025-06-14 | A Randomized, Double-Blind, 2-Treatment, 2-Period, Crossover Phase 1 Study to Compare the Pharmacokinetics, Safety and Tolerability of 60 IU/Kg of Abcertin and Cerezyme in Healthy Volunteers Following a Single Intravenous Administration.
Imiglucerase (Cerezyme; Sanofi, Paris, France), an analogue of β-glucocerebrosidase produced by recombinant DNA technology, has been a safe and effective treatment for Gaucher disease (GD) for over 25 years. A new imiglucerase, Abcertin (Seongnam-si, Gyeonggi-do, Republic of Korea) has shown a similar safety and efficacy profile in previous clinical studies. This study compared the pharmacokinetics, immunogenicity, safety, and tolerability to EU-sourced Cerezyme following a single 60 IU/kg dose. This phase 1, single-center, randomized, double-blind, two-way crossover study enrolled 36 healthy volunteers aged 18-45 years. Participants were randomly assigned to receive either Abcertin or Cerezyme in a predetermined sequence. Abcertin reached peak plasma concentrations at a median tmax of 61 min (range: 40-121 min). The mean Cmax, AUC0-last, and AUC0-inf were 115.4 mU/mL, 12,190 min·mU/mL, and 12,210 min mU/mL, respectively, indicating bioequivalence to Cerezyme. The mean t½, CL, and Vz were 6.88 min, 376.7 mL/min, and 3.62 L, respectively, and were comparable between the two treatments. One participant in the Cerezyme group developed anti-drug antibodies, which were non-neutralizing A total of 24 subjects experienced treatment-emergent adverse event (TEAE). The most common TEAE was headache (3 in the Abcertin group and 5 in the Cerezyme group), followed by general disorders and administration site condition (3 in Abcertin group and 5 in Cerezyme group). Two participants in the Cerezyme sequence experienced severe TEAEs: one had a urinary tract infection, and the other developed urticaria, which leading to study withdrawal. Abcertin demonstrated pharmacokinetic equivalence to Cerezyme, with a comparable safety, immunogenicity, and tolerability profile. These findings support its potential as an affordable biosimilar for GD treatment.
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Drug Discovery Landscape
37 orphan drug designations for Gaucher disease, including 5 approved therapies.
37 orphan drug designations for Gaucher disease, including 5 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
ambroxol | small molecules | FDA | LILA Holding AG | |
(S)-Quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate | small molecules | EMA | — | 3R Pharma Consulting GmbH |
selective glucosylceramide synthase (GCS) inhibitor | small molecules | FDA | Yuhan Corporation | |
adeno-associated viral vector delivering human GBA1 gene | gene therapies | FDA | Shanghai Vitalgen BioPharma Co., Ltd. | |
ambroxol | small molecules | FDA | Kalevala Therapeutics Inc. | |
ambroxol | small molecules | FDA | Agyany Pharma LTD. | |
Adeno-associated virus 9 vector expressing a functional human codon optimized cDNA encoding glucosylceramidase beta 1 | gene therapies | FDA | — | National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH) |
Ambroxol hydrochloride | small molecules | EMA | CATS Consultants GmbH | |
recombinant adeno-associated virus (rAAV) | gene therapies | FDA | Lingyi Biotech Co. Ltd. | |
Adeno-associated viral vector serotype S3 containing codon-optimised expression cassette encoding human beta-glucocerebrosidase variant | gene therapies | EMA | Spur Therapeutics (Ireland) Limited | |
Recombinant adeno-associated viral vector serotype S3 containing codon optimised expression cassette encoding human beta-glucocerebrosidase variant | gene therapies | FDA | Spur Therapeutics Limited | |
Adeno-associated viral vector serotype 9 expressing codon-optimized human GBA gene | gene therapies | EMA | PPD Bulgaria EOOD | |
AAV9 capsid encapsulating a bicistronic vector encoding for a unique combination of a recombinant human ?-glucocerebrosidase enzyme with the S1S3 variant of the N-acetylglucosamine-Phosphotransferase (S1S3 PTase) | gene therapies | FDA | — | M6P Therapeutics |
Autologous CD34+ cells transduced with a lentiviral vector encoding glucosylceramidase beta | gene therapies | EMA | — | PPD Bulgaria EOOD |
recombinant adeno-associated virus serotype 9 constitutively expressing codon optimized coding sequence of human GBA1 | gene therapies | FDA | Prevail Therapeutics | |
autologous CD34+ cell enriched hematopoietic stem cells genetically modified ex vivo with a lentiviral vector to contain codon-optimized complementary deoxyribonucleic acid that encodes human beta-glucocerebrosidase | cell therapies | FDA | AVROBIO, Inc. | |
Modified cholera toxin | proteins | FDA | — | ERAD Therapeutics, Inc. |
Adeno-associated viral vector serotype 9 containing the human glucocerebrosidase gene | gene therapies | EMA | — | The Gauchers Association Limited |
(3S)-1-azabicyclo[2.2.2]oct-3-yl{2-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]propan-2-yl}carbamate | small molecules | EMA | Sanofi B.V. | |
venglustat | small molecules | FDA | Genzyme | |
ambroxol | small molecules | FDA | Zywie LLC | |
Velaglucerase alfa [Vpriv] | proteins | EMA | Takeda Pharmaceuticals International AG | |
Taliglucerase alfa | proteins | EMA | Pfizer Europe MA EEIG | |
Taliglucerase alfa [ELELYSO for injection] | proteins | FDA | Approved | Pfizer, Inc. |
velaglucerase-alfa [VPRIV] | proteins | FDA | Approved | Takeda Development Center Americas, Inc. |
(1R, 2R)-Octanoic acid [2-(2’,3’-dihydro-benzo [1,4] dioxin-6’-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide-L-tartaric acid salt [Cerdelga] | small molecules | EMA | Approved | Sanofi B.V. |
Afegostat tartrate | small molecules | EMA | [INACTIVE] Amicus Therapeutics UK Limited | |
isofagomine tartrate | small molecules | FDA | Amicus Therapeutics, Inc. | |
Alendronate disodium | small molecules | FDA | Richard J. Wenstrup, M.D. | |
Miglustat [Zavesca] | small molecules | EMA | [INACTIVE] Actelion Registration Limited | |
miglustat [Zavesca] | small molecules | FDA | Approved | IC-MedTech Corporation |
Retroviral vector, R-GC and GC gene 1750 | gene therapies | FDA | — | Genzyme Corporation |
Alglucerase injection | proteins | FDA | Genzyme Corporation | |
Recombinant retroviral vector - glucocerebrosidase | gene therapies | FDA | — | Genetic Therapy, Inc. |
PEG-glucocerebrosidase | proteins | FDA | National Institute of Mental Health, NIH | |
Imiglucerase [Cerezyme] | proteins | FDA | Approved | Genzyme Corporation |
L-cycloserine | small molecules | FDA | — | Lev, Meir M.D. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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