RARE DISEASE
Gaucher disease type 1
Gaucher disease type 1
Gaucher disease type 1
Synonyms: Non-cerebral juvenile Gaucher disease
Synonyms: Non-cerebral juvenile Gaucher disease
Synonyms: Non-cerebral juvenile Gaucher disease
Drug discovery
3
drugs
With orphan designations
Overview
Gaucher disease type 1 (GD1) is an autosomal recessive lysosomal storage disorder caused by GBA gene mutations, resulting in deficient glucocerebrosidase activity and accumulation of glucocerebroside. It manifests with hepatosplenomegaly, cytopenias, bone complications (osteopenia, fractures), and fatigue, without primary neurological involvement [1][2][7]. Treatment focuses on enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) to mitigate visceral and hematological symptoms, though skeletal complications often persist [3][6][13].
Burden
Chronic complications: Bone pain, avascular necrosis, osteoporosis, and irreversible organ damage without early treatment [6][7][15]
Economic impact: Annual ERT costs exceed $200,000–$400,000 per patient [5][17]
Quality of life: Persistent fatigue, mobility limitations, and delayed growth/puberty in pediatric patients [9][15][19]
Therapies
ERT: Intravenous infusions (e.g., imiglucerase, velaglucerase) every 2 weeks to reduce substrate accumulation [1][6][17]
SRT: Oral agents (e.g., eliglustat, miglustat) to limit glucocerebroside synthesis [3][8][13]
Adjunctive care: Bisphosphonates for bone disease; transfusions for severe cytopenias [6][13]
Categories: rare bone diseases, rare cardiac diseases, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare respiratory diseases, rare systemic and rheumatological diseases, rare transplant-related disorders
Research Papers
1,477 drug discovery papers about Gaucher disease type 1, with 6 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,477 drug discovery papers about Gaucher disease type 1, with 6 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
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.
2024-12-30 | Current opinion on pluripotent stem cell technology in Gaucher's disease: challenges and future prospects.
Gaucher's disease (GD) is a rare autosomal recessive genetic disorder caused by mutations in the GBA1 gene. Mutations in the gene lead to the deficiency of glucocerebrosidase, an enzyme that helps in the breakdown of glucosylceramide (GlcCer) into ceramide and glucose. The lack of the enzyme causes GlcCer accumulation in macrophages, resulting in various phenotypic characteristics of GD. The currently available therapies, including enzyme replacement therapy and substrate reduction therapy, only provide symptomatic relief. However, they grapple with limitations in efficacy, accessibility, and potential side effects. These observations laid the foundation to search for new approaches in the management of GD. Induced pluripotent stem cells (iPSCs) technology emerges as a beacon of hope, offering novel avenues for future GD therapies. The true magic of iPSCs lies in their ability to differentiate into various cell types. By reprogramming patient-derived cells into iPSCs, researchers can generate personalized models that recapitulate the genetic and phenotypic characteristics of the GD. These models are valuable tools for dissecting intricate disease pathways, developing novel therapeutic targets, and enhancing the drug development process for GD. This review emphasizes the significance of iPSCs technology in GD management. Further, it addresses several challenges that are being encountered in the application of iPSC technology in the management of GD. In addition, it provides several insights into the future aspects of iPSC technology in the management of GD.
2024-10-03 | Therapeutic delivery of recombinant glucocerebrosidase enzyme-containing extracellular vesicles to human cells from Gaucher disease patients.
Gaucher disease (GD) is one of the most common types of lysosomal storage diseases (LSDs) caused by pathogenic variants of lysosomal β-glucocerebrosidase gene (GBA1), resulting in the impairment of Glucocerebrosidase (GCase) enzyme function and the accumulation of a glycolipid substrate, glucosylceramide (GlcCer) within lysosomes. Current therapeutic approaches such as enzyme replacement therapy and substrate reduction therapy cannot fully rescue GD pathologies, especially neurological symptoms. Meanwhile, delivery of lysosomal enzymes to the endocytic compartment of affected human cells is a promising strategy for treating neuropathic LSDs. Here, we describe a novel approach to restore GCase enzyme in cells from neuropathic GD patients by producing extracellular vesicle (EVs)-containing GCase from cells overexpressing GBA1 gene. Lentiviral vectors containing modified GBA1 were introduced into HEK293T cells to produce a stable cell line that provides a sustainable source of functional GCase enzyme. The GBA1-overexpressing cells released EV-containing GCase enzyme, that is capable of entering into and localizing in the endocytic compartment of recipient cells, including THP-1 macrophage, SH-SY5Y neuroblastoma, and macrophages and neurons derived from induced pluripotent stem cells (iPSCs) of neuropathic GD patients. Importantly, the recipient cells exhibit higher GCase enzyme activity. This study presents a promising therapeutic strategy to treat severe types of LSDs. It involves delivering lysosomal enzymes to the endocytic compartment of human cells affected by conditions such as GDs with neurological symptoms, as well as potentially other neurological disorders impacting lysosomes.
2024-08-01 | Hematopoietic stem cell transplantation or enzyme replacement therapy in Gaucher disease type 3.
Gaucher disease (GD) is a lysosomal storage disorder with glucocerebroside accumulation in the macrophages. The disease is divided into three types based on neurocognitive involvement with GD1 having no involvement while the acute (GD2) and chronic (GD3) are neuronopathic. The non-neurological symptoms of GD3 are well treated with enzyme replacement therapy (ERT) which has replaced hematopoietic stem cell transplantation (HSCT). ERT is unable to prevent neurological progression as the enzyme cannot cross the blood-brain barrier. In this retrospective study, we report the general, neurocognitive, and biochemical outcomes of three siblings with GD3 after treatment with ERT or HSCT. Two were treated with HSCT (named HSCT1 and HSCT2) and one with ERT (ERT1). All patients were homozygous for the c.1448 T > C, (p.Leu483Pro) variant in the GBA1 gene associated with GD3. ERT1 experienced neurocognitive progression with development of seizures, oculomotor apraxia, perceptive hearing loss and mental retardation. HSCT1 had no neurological manifestations, while HSCT2 developed perceptive hearing loss and low IQ. Chitotriosidase concentrations were normal in plasma and cerebrospinal fluid (CSF) for HSCT1 and HSCT2, but both were markedly elevated in ERT1. We report a better neurological outcome and a normalization of chitotriosidase in the two siblings treated with HSCT compared to the ERT-treated sibling. With the advancements in HSCT over the past 25 years, we may reconsider using HSCT in GD3 to achieve a better neurological outcome and limit disease progression.
small molecules
2026-09-27 | Ambroxol in Gaucher disease and GBA1-related Parkinson disease: an updated systematic review.
Ambroxol (ABX) is a central nervous system (CNS)-penetrant compound that can increase glucocerebrosidase activity and has been investigated in Gaucher disease (GD) and GBA1-related Parkinson disease (GBA1-PD). This PRISMA 2020 systematic review and narrative synthesis searched PubMed/MEDLINE, Europe PMC, SSRN and ClinicalTrials.gov through 19 August 2026, with an additional Web of Science Core Collection search performed during revision on 14 September 2026, without restrictions on date, language or publication status. Two reviewers independently selected studies, extracted data and assessed risk of bias using design-specific tools. Substantial clinical and methodological heterogeneity precluded meta-analysis RESULTS: Of 149 records in the original searches, 137 were screened, 41 full texts were assessed and 20 clinical outcome reports were included. The additional Web of Science search retrieved 50 records and did not identify further clinical outcome reports. Evidence in GD consisted mainly of small, uncontrolled and sometimes overlapping reports. Biochemical and neurological improvements were described in selected patients, but outcome definitions and functional responses varied. In GBA1-PD, conclusions remain provisional because the AMBITIOUS results are available only as a non-peer-reviewed preprint and did not show disease modification. Evidence on the safety of chronic high-dose treatment is limited. Biomarker changes alone do not establish clinical efficacy. ABX remains an off-label, investigational treatment in GD and GBA1-PD, and no GBA1 genotype or functional assay currently defines a validated indication.
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.
2026-09-19 | Computational evaluation of EPA-PC binding to GCase in neuronopathic Gaucher disease.
Gaucher disease (GD) is a lysosomal storage disorder caused by deficient acid β-glucosidase (GCase) activity and consequent accumulation of glucosylceramide. Current enzyme replacement and substrate reduction therapies improve several systemic manifestations but have limited impact on neuronopathic disease, motivating evaluation of alternative molecular strategies. This study computationally assessed the interaction of EPA-phosphatidylcholine (EPA-PC), a marine-derived omega-3 phospholipid, with human GCase (PDB ID: 2NSX). The protein structure was examined by Ramachandran analysis and hydrophobicity profiling, followed by AutoDock Vina engine docking at the proposed hydrophobic i-face. EPA-PC showed a docking score of -5.5 kcal/mol under the applied protocol. Independent PLIP profiling of the docked complex identified predominantly hydrophobic contacts, one hydrogen bond involving Phe347, and Arg395-mediated salt-bridge interactions. A single 200 ns molecular dynamics trajectory of the EPA-PC-GCase complex showed an apparent backbone RMSD plateau of approximately 0.35-0.40 nm and a radius of gyration near 2.4 nm without a sustained increase in global compactness or solvent exposure. These observations support persistence of the modelled complex during the reported trajectory but do not establish ligand-induced GCase stabilisation or pharmacological-chaperone activity. In silico ADMET profiling also indicated substantial liabilities, including very high plasma protein binding and predicted hERG-related risk. EPA-PC should therefore be regarded as a preliminary lipid-protein interaction model requiring comparative simulations, independent replicates, and experimental validation.
2026-09-18 | Early-onset parkinsonism as a presenting feature of suspected type 1 Gaucher disease with two pathogenic GBA1 variants: a case report.
Parkinson's disease (PD) is a common neurodegenerative disorder, and pathogenic variants in GBA1 are among its most frequent genetic risk factors. Biallelic pathogenic GBA1 variants cause Gaucher Disease (GD). In patients with parkinsonism and two detected GBA1 variants, the absence of biochemical confirmation and allele phasing may make it difficult to determine whether the neurological presentation occurs in the context of GD or represents GBA1-associated PD. We report a 35-year-old man with a 7-months history of progressive, asymmetric parkinsonism. Dopamine transporter PET/CT showed reduced bilateral striatal uptake, more pronounced on the right. Abdominal CT showed asplenia, and laboratory eveluation revealed mild thrombocytopenia, marked hyperferritinemia, polyclonal hypergammaglobulinemia, proteinuria, and microscopic hematuria. Whole-exome sequencing followed by Sanger validation identified two heterozygous GBA1 variants classified as pathogenic: c.1448T>C (p.Leu483Pro; legacy name L444P) and c.1342G>C (p.Asp448His; legacy name D409H). Family testing supported the familial occurrence of both variants but did not establish their allelic phase. Because glucocerebrosidase activity and GD biomarkers were not measured, type 1 Gaucher disease (GD1) remained suspected rather than confirmed. During hospitalization, dopaminergic therapy was associated with clinical improvement, with the OFF-state UPDRS-III score decreasing from 21 at admission to 10 at discharge. The clinical value of this case lies in the convergence of early-onset parkinsonism, remote visceral and hematologic findings, the co-occurrence of p.Leu483Pro and p.Asp448His with unresolved allelic phase, and the familial occurrence of both variants. It underscores the need for biochemical confirmation, GBA1-specific phase-resolved testing, and longitudinal multisystem assessment before the diagnosis of GD1 and the associated familial risks can be reliably defined.
2026-09-18 | GBA1 in Parkinson's disease: past, present and future.
GBA1 variants represent some of the most important genetic risk factors for Parkinson's disease (PD), present in a substantial proportion of patients across populations. This review provides a comprehensive overview of the field, tracing the historical path from the first description of Gaucher disease (GD) in 1882 to the recognition of GBA1 as a key contributor to PD risk, and highlighting major scientific and translational milestones along the way. We summarize current understanding of the biological mechanisms linking GBA1 to PD, including both loss-of-function and gain-of-function hypotheses, and discuss how reduced glucocerebrosidase (GCase) activity may lead to α-synuclein accumulation and neurodegeneration. Remaining gaps in knowledge, especially regarding downstream lipidomic effects and cell-type-specific mechanisms, are emphasized as key priorities for future research. This review also examines clinical and translational advances, including the development of GCase-targeted therapies such as small molecules, chaperones, substrate reduction therapies, and gene-based approaches. We discuss outcomes from recent and ongoing clinical trials, highlighting both promising strategies and notable failures that inform our evolving understanding of disease biology. In addition, we address the heterogeneity of PD and the importance of stratifying patients based on genetic background. Finally, we outline critical challenges and future directions, including the need for precision medicine approaches based on variant-specific mechanisms, improved biomarkers to define true GBA1-associated PD, and optimized clinical trial design. We propose that coordinated, open-science efforts and large-scale collaborative frameworks will be essential to accelerate discovery and translate mechanistic insights into effective disease-modifying therapies.
gene therapies
2026-07-09 | Intra-CNS AAV9-GBA1 delivery yields species and route of administration differences in safety and transgene expression.
Adeno-associated virus (AAV) delivery of lysosomal enzymes to the brain is currently being tested in several clinical trials. However, publicly available non-human primate (NHP) studies comprehensively reporting biodistribution, transgene expression, and safety across the central nervous system (CNS) remain limited. Here, we examined AAV9-GBA1 (encoding glucocerebrosidase [GCase]) delivery to mice and NHPs. Loss-of-function GBA1 mutations cause Gaucher's disease and are risk factors for Parkinson's disease and dementia with Lewy bodies. In mice, early postnatal intracerebroventricular administration produced appreciable transgene expression and increased GCase activity in the brain without adverse findings. Two independent adult NHP studies evaluated AAV9-GBA1 brain delivery via intracisterna magna (ICM) and intraparenchymal (IPa) administration. ICM delivery produced considerable transgene expression in the spinal cord and dorsal root ganglia (DRG) neurons along with adverse microscopic findings, but limited brain expression and activity. In contrast, IPa delivery into the thalamus and/or putamen produced substantial transgene expression and GCase activity in injected and connected brain regions, with limited effects in distal regions, including the spinal cord. While no AAV-related DRG toxicity was detected with IPa, procedure- and AAV9-GBA1-related adverse microscopic brain findings were observed and associated with clinical outcomes. Further technological advances are needed to achieve safe and therapeutic AAV transgene expression in NHP brain.
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.
2026-01-01 | 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.
2025-12-11 | AAV gene therapy for GBA1-related diseases.
Mutations in GBA1, the gene encoding glucocerebrosidase (GCase), are the most common risk factor for Parkinson's disease (PD). GBA-PD patients are a genetic subpopulation of PD carrying heterozygous mutations in GBA1. Additionally, bi-allelic mutations in GBA1 cause Gaucher disease (GD), a lysosomal storage disorder. Loss of GCase activity, a lysosomal enzyme, leads to the accumulation of lipid substrates, disrupting lipid homeostasis and causing lysosomal dysfunction. Here, we report an AAV-mediated GBA1 replacement strategy to treat diseases arising from mutations in GBA1. We engineered human GCase to be readily secretable to facilitate broad cross-correction. We developed CBE (conduritol β-epoxide)-induced lipid accumulation models to assess efficacy in mice and non-human primates (NHPs). Based on data across species, we nominated AAV.GMU01 SS3-GBA1 as our lead candidate. SS3-GBA1 is robustly secreted, cross-corrects across tissues and promotes lipid clearance. By comparing human GCase levels in AAV-treated NHP brains to healthy human donor brains, we demonstrate that AAV.GMU01 SS3-GBA1 replenishes the GCase deficit seen in GBA-PD patients, thus restoring GCase to near-physiological levels. Importantly, AAV.GMU01 SS3-GBA1 is well tolerated with no adverse findings. Collectively, we establish a therapeutic strategy for the treatment of GD and GBA-associated PD with a single-gene therapy product.
proteins
2026-09-08 | Clinical and genetic landscape of neuronopathic gaucher disease in Ukraine: hepatosplenomegaly and diagnostic delay.
Neuronopathic Gaucher disease (GD types II and III) represents rare and severe phenotypes of glucocerebrosidase deficiency, characterized by neurological involvement and variable systemic manifestations. Data on clinical presentation and genotype-phenotype patterns in Eastern European populations remain limited. We conducted a retrospective cohort study of 92 patients with confirmed Gaucher disease followed at the National Children's Specialized Hospital "Okhmatdyt" (Kyiv, Ukraine) between 2001 and 2024. Among them, 4 patients had type II and 6 had type III GD. Diagnosis was established by measurement of leukocyte β-glucocerebrosidase activity and molecular analysis of the GBA1 gene. Clinical, laboratory, and imaging data were analyzed descriptively. Type II GD presented in early infancy, with symptom onset from birth to 5 months of age (mean age at onset 2.8 ± 2.6 months) and was diagnosed between 5 and 9 months of age (mean 7.0 ± 2.3 months). Initial manifestations included cytopenias, splenomegaly, failure to thrive, and ichthyosiform dermatitis. Hepatomegaly was uncommon at onset, but hepatosplenomegaly was documented in all patients at diagnosis, followed by rapid neurological regression and death by 14 months of age. Type III GD had a mean age at onset of 2.3 ± 1.66 years and a mean age at diagnosis of 13.8 ± 16.87 years, reflecting substantial diagnostic delay. Oculomotor abnormalities were the most frequent presenting manifestations (83%). At diagnosis, all patients exhibited hepatosplenomegaly, cytopenias, and neurological involvement, while liver function remained preserved. Across both phenotypes, GBA1 variant combinations included genotypes predicted to result in very low or absent residual glucocerebrosidase activity, as well as genotypes predicted to retain some residual activity. Severe clinical courses were observed even in patients whose genotypes were predicted to retain residual enzyme activity, suggesting that predicted residual activity alone does not reliably explain clinical severity. In this Ukrainian cohort, neuronopathic GD demonstrated distinct clinical trajectories, with rapidly progressive infantile disease in type II and heterogeneous presentation with marked diagnostic delay in type III. Hepatosplenomegaly was a common systemic feature during disease progression, but should not be interpreted as an isolated stratifying sign. Its presence, particularly in combination with early or progressive neurological manifestations, should raise suspicion of neuronopathic GD.
2026-08-04 | Industry Insights: Expanding access across the field, from pediatric approvals to the first solid tumor CAR‑T
July 2026 saw the field push access outward on multiple fronts, from the first FDA approval of a genetic therapy for children as young as 2 years (Vertex’s CASGEVY) to the first international patient treated with satri‑cel, the first CAR‑T therapy approved anywhere for a solid tumor. Regulatory momentum extended across in vivo CAR‑T, allogeneic transplant, and solid tumor cell therapy, while ARPA‑H committed up to $160 million to scalable in vivo gene editing for rare diseases. Alongside these milestones, new partnerships, a €33 million financing, and first patient dosings in pivotal trials for Gaucher disease type 1 and diabetic retinopathy signaled continued investment across the manufacturing, clinical, and commercial landscape.
2026-05-01 | B73-44 To Pull or Not to Pull? Successful Empyema Therapy Despite Persistent Drainage
Abstract Background Determining when to remove a chest tube in empyema remains debated, particularly when daily drainage exceeds traditional thresholds. While conventional practice favors removal when output is < 100-150 mL/day, individualized and clinically-guided decisions are increasingly warranted and supported. Case Presentation A 62-year-old man with PMH of Type I Gaucher disease, chronic thrombocytopenia, HTN, and obesity presented with a three-week history of productive cough and fatigue. Chest CT revealed a multiloculated right-sided pleural effusion with adjacent area of necrosis in the right lower lobe [FIGURE-1]. Pleural fluid was pinkish-brown and turbid with pH <6.8, WBC 259,000/µL (91% neutrophils), RBC 278,000/µL, LDH >7500 U/L, and protein 3.9 g/dL. Findings were consistent with a complicated exudative pleural effusion. Etiology was likely anerobic empyema & pneumonia with visceral pleural perforation leading to hydropneumothorax. He underwent CT-guided chest tube placement for source control with three days of intrapleural tPA/DNase therapy to assist with drainage. Additionally, he received IV vancomycin and piperacillin-tazobactam during his one-week hospital stay. The patient showed marked clinical and radiographic improvement, allowing transition to oral amoxicillin-clavulanate and doxycycline. The chest tube remained in place for six days, with persistent output of approximately 200 mL/day of non-purulent serous fluid at the time of removal. Given stability, improved imaging, and normalization of inflammatory markers, the chest tube was safely removed. He completed an additional seven weeks of oral antibiotic therapy following discharge. Outpatient follow-up CT demonstrated continued resolution of the pleural space infection with no recurrence and no further complications [FIGURE-2]. Discussion This case underscores the evolving paradigm in empyema management, where clinical trajectory and imaging findings often outweigh fixed numeric thresholds for chest tube removal. Although traditional criteria recommend drainage <150 mL/day for chest tube removal, several studies suggest that sterile and non-purulent serous output may not necessitate prolonged drainage if radiographic improvement and patient recovery are evident. Prolonged tube placement can increase pain, infection risk, complication risk, and hospital stay. In this patient, early removal despite moderate output resulted in full resolution and no recurrence. Individualized, multidisciplinary decision-making—incorporating pleural fluid characteristics, patient comorbidities, and dynamic imaging assessment—can optimize outcomes and reduce unnecessary interventions in complex pleural infections. This abstract is funded by: None
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.
2026-04-12 | Effect of Glu235Ser on enzyme performance and in vitro characterization of human β-glucocerebrosidase in a Pichia pastoris.
Gaucher disease (GD) is the most common lysosomal storage disorder and is caused by inherited deficiency of β-glucocerebrosidase (GCase), resulting in glucocerebroside accumulation in multiple organs. Enzyme replacement therapy (ERT) is associated with complex and costly manufacturing processes, which has motivated the development of scalable expression systems. This study investigates recombinant production of human GCase using the Pichia pastoris GlycoSwitch® platform. The human β-glucocerebrosidase (gba) gene was cloned and expressed to generate both wild-type (WT) and mutant (Glu235Ser) GCase as functional glycoproteins. Both enzymes were purified and characterized using biochemical, kinetic, and computational analyses. The mutant exhibited higher catalytic efficiency, showing ~20 and ~10-fold increases in kcat/KM toward pNPG and 4-MUG, respectively, compared with WT. Both enzymes retained a similar optimal pH (8.0), while the mutant showed higher residual activity at elevated temperatures, retaining 50-60% activity with an optimal range of 60-70 °C. Structural modeling of the Glu235Ser variant suggested that catalysis might involve a His-Asp dyad mechanism. Modeling also indicated that the boat conformation of pNPG is both energetically favorable and catalytically preferred. In vitro assays indicated approximately 2-fold higher activity retention of the mutant under acidic and short-term plasma incubation conditions. In PMA-differentiated U937 macrophage-like cells, the mutant showed increased cellular uptake and prolonged intracellular activity compared to the wild-type enzyme; however, these effects may not be solely attributed to the mutation and may also be influenced by differences in glycosylation or other factors.
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.
2025-05-30 | A Multiomic Network Approach to Uncover Disease Modifying Mechanisms of Inborn Errors of Metabolism.
For many inborn errors of metabolism (IEM) the understanding of disease mechanisms remains limited, in part explaining their unmet medical needs. The expressivity of IEM disease phenotypes is affected by disease-modifying factors, including rare and common polygenic variation. We hypothesize that we can identify these modulating pathways using molecular signatures of IEM in combination with multiomic data and gene regulatory networks generated from non-IEM animal and human populations. We tested this approach by identifying and subsequently validating glucocorticoid signaling as a candidate modifier of mitochondrial fatty acid oxidation disorders, and recapitulating complement signaling as a modifier of inflammation in Gaucher disease. Our work describes a novel approach that can overcome the rare disease-rare data dilemma and reveal new IEM pathophysiology and potential drug targets using multiomics data in seemingly healthy populations.
2025-05-28 | Developing nanobodies as allosteric molecular chaperones of glucocerebrosidase function.
The enzyme glucocerebrosidase (GCase) catalyses the hydrolysis of glucosylceramide to glucose and ceramide within lysosomes. Homozygous or compound heterozygous mutations in the GCase-encoding GBA1 gene cause the lysosomal storage disorder Gaucher disease, while heterozygous and homozygous mutations are the most frequent genetic risk factor for Parkinson's disease. These mutations commonly affect GCase stability, trafficking or activity. Here, we report the development and characterization of nanobodies (Nbs) targeting and acting as molecular chaperones for GCase. We identify several Nb families that bind with nanomolar affinity to GCase. Based on biochemical characterization, we group the Nbs in two classes: Nbs that improve the activity of the enzyme and Nbs that increase GCase stability in vitro. A selection of the most promising Nbs is shown to improve GCase function in cell models and positively impact the activity of the N370S mutant GCase. These results lay the foundation for the development of new therapeutic routes.
2024-12-13 | African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1.
Recently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (GBA1). This variant ( rs3115534 -G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups but is almost absent in European and Asian ancestry populations. GBA1 is a gene of high clinical and therapeutic interest. Damaging biallelic protein-coding variants cause Gaucher disease and monoallelic variants confer risk for PD and dementia with Lewy bodies, likely by reducing the function of glucocerebrosidase. Interestingly, the African ancestry-specific GBA1 risk variant is a noncoding variant, suggesting a different mechanism of action. Using full-length RNA transcript sequencing, we identified partial intron 8 expression in risk variant carriers (G) but not in nonvariant carriers (T). Antibodies targeting the N terminus of glucocerebrosidase showed that this intron-retained isoform is likely not protein coding and subsequent proteomics did not identify a shorter protein isoform, suggesting that the disease mechanism is RNA based. Clustered regularly interspaced short palindromic repeats editing of the reported index variant ( rs3115534 ) revealed that this is the sequence alteration responsible for driving the production of these transcripts containing intron 8. Follow-up analysis of this variant showed that it is in a key intronic branchpoint sequence and, therefore, has important implications in splicing and disease. In addition, when measuring glucocerebrosidase activity, we identified a dose-dependent reduction in risk variant carriers. Overall, we report the functional effect of a GBA1 noncoding risk variant, which acts by interfering with the splicing of functional GBA1 transcripts, resulting in reduced protein levels and reduced glucocerebrosidase activity. This understanding reveals a potential therapeutic target in an underserved and underrepresented population.
cell therapies
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.
2024-12-30 | Current opinion on pluripotent stem cell technology in Gaucher's disease: challenges and future prospects.
Gaucher's disease (GD) is a rare autosomal recessive genetic disorder caused by mutations in the GBA1 gene. Mutations in the gene lead to the deficiency of glucocerebrosidase, an enzyme that helps in the breakdown of glucosylceramide (GlcCer) into ceramide and glucose. The lack of the enzyme causes GlcCer accumulation in macrophages, resulting in various phenotypic characteristics of GD. The currently available therapies, including enzyme replacement therapy and substrate reduction therapy, only provide symptomatic relief. However, they grapple with limitations in efficacy, accessibility, and potential side effects. These observations laid the foundation to search for new approaches in the management of GD. Induced pluripotent stem cells (iPSCs) technology emerges as a beacon of hope, offering novel avenues for future GD therapies. The true magic of iPSCs lies in their ability to differentiate into various cell types. By reprogramming patient-derived cells into iPSCs, researchers can generate personalized models that recapitulate the genetic and phenotypic characteristics of the GD. These models are valuable tools for dissecting intricate disease pathways, developing novel therapeutic targets, and enhancing the drug development process for GD. This review emphasizes the significance of iPSCs technology in GD management. Further, it addresses several challenges that are being encountered in the application of iPSC technology in the management of GD. In addition, it provides several insights into the future aspects of iPSC technology in the management of GD.
2024-10-03 | Therapeutic delivery of recombinant glucocerebrosidase enzyme-containing extracellular vesicles to human cells from Gaucher disease patients.
Gaucher disease (GD) is one of the most common types of lysosomal storage diseases (LSDs) caused by pathogenic variants of lysosomal β-glucocerebrosidase gene (GBA1), resulting in the impairment of Glucocerebrosidase (GCase) enzyme function and the accumulation of a glycolipid substrate, glucosylceramide (GlcCer) within lysosomes. Current therapeutic approaches such as enzyme replacement therapy and substrate reduction therapy cannot fully rescue GD pathologies, especially neurological symptoms. Meanwhile, delivery of lysosomal enzymes to the endocytic compartment of affected human cells is a promising strategy for treating neuropathic LSDs. Here, we describe a novel approach to restore GCase enzyme in cells from neuropathic GD patients by producing extracellular vesicle (EVs)-containing GCase from cells overexpressing GBA1 gene. Lentiviral vectors containing modified GBA1 were introduced into HEK293T cells to produce a stable cell line that provides a sustainable source of functional GCase enzyme. The GBA1-overexpressing cells released EV-containing GCase enzyme, that is capable of entering into and localizing in the endocytic compartment of recipient cells, including THP-1 macrophage, SH-SY5Y neuroblastoma, and macrophages and neurons derived from induced pluripotent stem cells (iPSCs) of neuropathic GD patients. Importantly, the recipient cells exhibit higher GCase enzyme activity. This study presents a promising therapeutic strategy to treat severe types of LSDs. It involves delivering lysosomal enzymes to the endocytic compartment of human cells affected by conditions such as GDs with neurological symptoms, as well as potentially other neurological disorders impacting lysosomes.
2024-08-01 | Hematopoietic stem cell transplantation or enzyme replacement therapy in Gaucher disease type 3.
Gaucher disease (GD) is a lysosomal storage disorder with glucocerebroside accumulation in the macrophages. The disease is divided into three types based on neurocognitive involvement with GD1 having no involvement while the acute (GD2) and chronic (GD3) are neuronopathic. The non-neurological symptoms of GD3 are well treated with enzyme replacement therapy (ERT) which has replaced hematopoietic stem cell transplantation (HSCT). ERT is unable to prevent neurological progression as the enzyme cannot cross the blood-brain barrier. In this retrospective study, we report the general, neurocognitive, and biochemical outcomes of three siblings with GD3 after treatment with ERT or HSCT. Two were treated with HSCT (named HSCT1 and HSCT2) and one with ERT (ERT1). All patients were homozygous for the c.1448 T > C, (p.Leu483Pro) variant in the GBA1 gene associated with GD3. ERT1 experienced neurocognitive progression with development of seizures, oculomotor apraxia, perceptive hearing loss and mental retardation. HSCT1 had no neurological manifestations, while HSCT2 developed perceptive hearing loss and low IQ. Chitotriosidase concentrations were normal in plasma and cerebrospinal fluid (CSF) for HSCT1 and HSCT2, but both were markedly elevated in ERT1. We report a better neurological outcome and a normalization of chitotriosidase in the two siblings treated with HSCT compared to the ERT-treated sibling. With the advancements in HSCT over the past 25 years, we may reconsider using HSCT in GD3 to achieve a better neurological outcome and limit disease progression.
small molecules
2026-09-27 | Ambroxol in Gaucher disease and GBA1-related Parkinson disease: an updated systematic review.
Ambroxol (ABX) is a central nervous system (CNS)-penetrant compound that can increase glucocerebrosidase activity and has been investigated in Gaucher disease (GD) and GBA1-related Parkinson disease (GBA1-PD). This PRISMA 2020 systematic review and narrative synthesis searched PubMed/MEDLINE, Europe PMC, SSRN and ClinicalTrials.gov through 19 August 2026, with an additional Web of Science Core Collection search performed during revision on 14 September 2026, without restrictions on date, language or publication status. Two reviewers independently selected studies, extracted data and assessed risk of bias using design-specific tools. Substantial clinical and methodological heterogeneity precluded meta-analysis RESULTS: Of 149 records in the original searches, 137 were screened, 41 full texts were assessed and 20 clinical outcome reports were included. The additional Web of Science search retrieved 50 records and did not identify further clinical outcome reports. Evidence in GD consisted mainly of small, uncontrolled and sometimes overlapping reports. Biochemical and neurological improvements were described in selected patients, but outcome definitions and functional responses varied. In GBA1-PD, conclusions remain provisional because the AMBITIOUS results are available only as a non-peer-reviewed preprint and did not show disease modification. Evidence on the safety of chronic high-dose treatment is limited. Biomarker changes alone do not establish clinical efficacy. ABX remains an off-label, investigational treatment in GD and GBA1-PD, and no GBA1 genotype or functional assay currently defines a validated indication.
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.
2026-09-19 | Computational evaluation of EPA-PC binding to GCase in neuronopathic Gaucher disease.
Gaucher disease (GD) is a lysosomal storage disorder caused by deficient acid β-glucosidase (GCase) activity and consequent accumulation of glucosylceramide. Current enzyme replacement and substrate reduction therapies improve several systemic manifestations but have limited impact on neuronopathic disease, motivating evaluation of alternative molecular strategies. This study computationally assessed the interaction of EPA-phosphatidylcholine (EPA-PC), a marine-derived omega-3 phospholipid, with human GCase (PDB ID: 2NSX). The protein structure was examined by Ramachandran analysis and hydrophobicity profiling, followed by AutoDock Vina engine docking at the proposed hydrophobic i-face. EPA-PC showed a docking score of -5.5 kcal/mol under the applied protocol. Independent PLIP profiling of the docked complex identified predominantly hydrophobic contacts, one hydrogen bond involving Phe347, and Arg395-mediated salt-bridge interactions. A single 200 ns molecular dynamics trajectory of the EPA-PC-GCase complex showed an apparent backbone RMSD plateau of approximately 0.35-0.40 nm and a radius of gyration near 2.4 nm without a sustained increase in global compactness or solvent exposure. These observations support persistence of the modelled complex during the reported trajectory but do not establish ligand-induced GCase stabilisation or pharmacological-chaperone activity. In silico ADMET profiling also indicated substantial liabilities, including very high plasma protein binding and predicted hERG-related risk. EPA-PC should therefore be regarded as a preliminary lipid-protein interaction model requiring comparative simulations, independent replicates, and experimental validation.
2026-09-18 | Early-onset parkinsonism as a presenting feature of suspected type 1 Gaucher disease with two pathogenic GBA1 variants: a case report.
Parkinson's disease (PD) is a common neurodegenerative disorder, and pathogenic variants in GBA1 are among its most frequent genetic risk factors. Biallelic pathogenic GBA1 variants cause Gaucher Disease (GD). In patients with parkinsonism and two detected GBA1 variants, the absence of biochemical confirmation and allele phasing may make it difficult to determine whether the neurological presentation occurs in the context of GD or represents GBA1-associated PD. We report a 35-year-old man with a 7-months history of progressive, asymmetric parkinsonism. Dopamine transporter PET/CT showed reduced bilateral striatal uptake, more pronounced on the right. Abdominal CT showed asplenia, and laboratory eveluation revealed mild thrombocytopenia, marked hyperferritinemia, polyclonal hypergammaglobulinemia, proteinuria, and microscopic hematuria. Whole-exome sequencing followed by Sanger validation identified two heterozygous GBA1 variants classified as pathogenic: c.1448T>C (p.Leu483Pro; legacy name L444P) and c.1342G>C (p.Asp448His; legacy name D409H). Family testing supported the familial occurrence of both variants but did not establish their allelic phase. Because glucocerebrosidase activity and GD biomarkers were not measured, type 1 Gaucher disease (GD1) remained suspected rather than confirmed. During hospitalization, dopaminergic therapy was associated with clinical improvement, with the OFF-state UPDRS-III score decreasing from 21 at admission to 10 at discharge. The clinical value of this case lies in the convergence of early-onset parkinsonism, remote visceral and hematologic findings, the co-occurrence of p.Leu483Pro and p.Asp448His with unresolved allelic phase, and the familial occurrence of both variants. It underscores the need for biochemical confirmation, GBA1-specific phase-resolved testing, and longitudinal multisystem assessment before the diagnosis of GD1 and the associated familial risks can be reliably defined.
2026-09-18 | GBA1 in Parkinson's disease: past, present and future.
GBA1 variants represent some of the most important genetic risk factors for Parkinson's disease (PD), present in a substantial proportion of patients across populations. This review provides a comprehensive overview of the field, tracing the historical path from the first description of Gaucher disease (GD) in 1882 to the recognition of GBA1 as a key contributor to PD risk, and highlighting major scientific and translational milestones along the way. We summarize current understanding of the biological mechanisms linking GBA1 to PD, including both loss-of-function and gain-of-function hypotheses, and discuss how reduced glucocerebrosidase (GCase) activity may lead to α-synuclein accumulation and neurodegeneration. Remaining gaps in knowledge, especially regarding downstream lipidomic effects and cell-type-specific mechanisms, are emphasized as key priorities for future research. This review also examines clinical and translational advances, including the development of GCase-targeted therapies such as small molecules, chaperones, substrate reduction therapies, and gene-based approaches. We discuss outcomes from recent and ongoing clinical trials, highlighting both promising strategies and notable failures that inform our evolving understanding of disease biology. In addition, we address the heterogeneity of PD and the importance of stratifying patients based on genetic background. Finally, we outline critical challenges and future directions, including the need for precision medicine approaches based on variant-specific mechanisms, improved biomarkers to define true GBA1-associated PD, and optimized clinical trial design. We propose that coordinated, open-science efforts and large-scale collaborative frameworks will be essential to accelerate discovery and translate mechanistic insights into effective disease-modifying therapies.
gene therapies
2026-07-09 | Intra-CNS AAV9-GBA1 delivery yields species and route of administration differences in safety and transgene expression.
Adeno-associated virus (AAV) delivery of lysosomal enzymes to the brain is currently being tested in several clinical trials. However, publicly available non-human primate (NHP) studies comprehensively reporting biodistribution, transgene expression, and safety across the central nervous system (CNS) remain limited. Here, we examined AAV9-GBA1 (encoding glucocerebrosidase [GCase]) delivery to mice and NHPs. Loss-of-function GBA1 mutations cause Gaucher's disease and are risk factors for Parkinson's disease and dementia with Lewy bodies. In mice, early postnatal intracerebroventricular administration produced appreciable transgene expression and increased GCase activity in the brain without adverse findings. Two independent adult NHP studies evaluated AAV9-GBA1 brain delivery via intracisterna magna (ICM) and intraparenchymal (IPa) administration. ICM delivery produced considerable transgene expression in the spinal cord and dorsal root ganglia (DRG) neurons along with adverse microscopic findings, but limited brain expression and activity. In contrast, IPa delivery into the thalamus and/or putamen produced substantial transgene expression and GCase activity in injected and connected brain regions, with limited effects in distal regions, including the spinal cord. While no AAV-related DRG toxicity was detected with IPa, procedure- and AAV9-GBA1-related adverse microscopic brain findings were observed and associated with clinical outcomes. Further technological advances are needed to achieve safe and therapeutic AAV transgene expression in NHP brain.
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.
2026-01-01 | 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.
2025-12-11 | AAV gene therapy for GBA1-related diseases.
Mutations in GBA1, the gene encoding glucocerebrosidase (GCase), are the most common risk factor for Parkinson's disease (PD). GBA-PD patients are a genetic subpopulation of PD carrying heterozygous mutations in GBA1. Additionally, bi-allelic mutations in GBA1 cause Gaucher disease (GD), a lysosomal storage disorder. Loss of GCase activity, a lysosomal enzyme, leads to the accumulation of lipid substrates, disrupting lipid homeostasis and causing lysosomal dysfunction. Here, we report an AAV-mediated GBA1 replacement strategy to treat diseases arising from mutations in GBA1. We engineered human GCase to be readily secretable to facilitate broad cross-correction. We developed CBE (conduritol β-epoxide)-induced lipid accumulation models to assess efficacy in mice and non-human primates (NHPs). Based on data across species, we nominated AAV.GMU01 SS3-GBA1 as our lead candidate. SS3-GBA1 is robustly secreted, cross-corrects across tissues and promotes lipid clearance. By comparing human GCase levels in AAV-treated NHP brains to healthy human donor brains, we demonstrate that AAV.GMU01 SS3-GBA1 replenishes the GCase deficit seen in GBA-PD patients, thus restoring GCase to near-physiological levels. Importantly, AAV.GMU01 SS3-GBA1 is well tolerated with no adverse findings. Collectively, we establish a therapeutic strategy for the treatment of GD and GBA-associated PD with a single-gene therapy product.
proteins
2026-09-08 | Clinical and genetic landscape of neuronopathic gaucher disease in Ukraine: hepatosplenomegaly and diagnostic delay.
Neuronopathic Gaucher disease (GD types II and III) represents rare and severe phenotypes of glucocerebrosidase deficiency, characterized by neurological involvement and variable systemic manifestations. Data on clinical presentation and genotype-phenotype patterns in Eastern European populations remain limited. We conducted a retrospective cohort study of 92 patients with confirmed Gaucher disease followed at the National Children's Specialized Hospital "Okhmatdyt" (Kyiv, Ukraine) between 2001 and 2024. Among them, 4 patients had type II and 6 had type III GD. Diagnosis was established by measurement of leukocyte β-glucocerebrosidase activity and molecular analysis of the GBA1 gene. Clinical, laboratory, and imaging data were analyzed descriptively. Type II GD presented in early infancy, with symptom onset from birth to 5 months of age (mean age at onset 2.8 ± 2.6 months) and was diagnosed between 5 and 9 months of age (mean 7.0 ± 2.3 months). Initial manifestations included cytopenias, splenomegaly, failure to thrive, and ichthyosiform dermatitis. Hepatomegaly was uncommon at onset, but hepatosplenomegaly was documented in all patients at diagnosis, followed by rapid neurological regression and death by 14 months of age. Type III GD had a mean age at onset of 2.3 ± 1.66 years and a mean age at diagnosis of 13.8 ± 16.87 years, reflecting substantial diagnostic delay. Oculomotor abnormalities were the most frequent presenting manifestations (83%). At diagnosis, all patients exhibited hepatosplenomegaly, cytopenias, and neurological involvement, while liver function remained preserved. Across both phenotypes, GBA1 variant combinations included genotypes predicted to result in very low or absent residual glucocerebrosidase activity, as well as genotypes predicted to retain some residual activity. Severe clinical courses were observed even in patients whose genotypes were predicted to retain residual enzyme activity, suggesting that predicted residual activity alone does not reliably explain clinical severity. In this Ukrainian cohort, neuronopathic GD demonstrated distinct clinical trajectories, with rapidly progressive infantile disease in type II and heterogeneous presentation with marked diagnostic delay in type III. Hepatosplenomegaly was a common systemic feature during disease progression, but should not be interpreted as an isolated stratifying sign. Its presence, particularly in combination with early or progressive neurological manifestations, should raise suspicion of neuronopathic GD.
2026-08-04 | Industry Insights: Expanding access across the field, from pediatric approvals to the first solid tumor CAR‑T
July 2026 saw the field push access outward on multiple fronts, from the first FDA approval of a genetic therapy for children as young as 2 years (Vertex’s CASGEVY) to the first international patient treated with satri‑cel, the first CAR‑T therapy approved anywhere for a solid tumor. Regulatory momentum extended across in vivo CAR‑T, allogeneic transplant, and solid tumor cell therapy, while ARPA‑H committed up to $160 million to scalable in vivo gene editing for rare diseases. Alongside these milestones, new partnerships, a €33 million financing, and first patient dosings in pivotal trials for Gaucher disease type 1 and diabetic retinopathy signaled continued investment across the manufacturing, clinical, and commercial landscape.
2026-05-01 | B73-44 To Pull or Not to Pull? Successful Empyema Therapy Despite Persistent Drainage
Abstract Background Determining when to remove a chest tube in empyema remains debated, particularly when daily drainage exceeds traditional thresholds. While conventional practice favors removal when output is < 100-150 mL/day, individualized and clinically-guided decisions are increasingly warranted and supported. Case Presentation A 62-year-old man with PMH of Type I Gaucher disease, chronic thrombocytopenia, HTN, and obesity presented with a three-week history of productive cough and fatigue. Chest CT revealed a multiloculated right-sided pleural effusion with adjacent area of necrosis in the right lower lobe [FIGURE-1]. Pleural fluid was pinkish-brown and turbid with pH <6.8, WBC 259,000/µL (91% neutrophils), RBC 278,000/µL, LDH >7500 U/L, and protein 3.9 g/dL. Findings were consistent with a complicated exudative pleural effusion. Etiology was likely anerobic empyema & pneumonia with visceral pleural perforation leading to hydropneumothorax. He underwent CT-guided chest tube placement for source control with three days of intrapleural tPA/DNase therapy to assist with drainage. Additionally, he received IV vancomycin and piperacillin-tazobactam during his one-week hospital stay. The patient showed marked clinical and radiographic improvement, allowing transition to oral amoxicillin-clavulanate and doxycycline. The chest tube remained in place for six days, with persistent output of approximately 200 mL/day of non-purulent serous fluid at the time of removal. Given stability, improved imaging, and normalization of inflammatory markers, the chest tube was safely removed. He completed an additional seven weeks of oral antibiotic therapy following discharge. Outpatient follow-up CT demonstrated continued resolution of the pleural space infection with no recurrence and no further complications [FIGURE-2]. Discussion This case underscores the evolving paradigm in empyema management, where clinical trajectory and imaging findings often outweigh fixed numeric thresholds for chest tube removal. Although traditional criteria recommend drainage <150 mL/day for chest tube removal, several studies suggest that sterile and non-purulent serous output may not necessitate prolonged drainage if radiographic improvement and patient recovery are evident. Prolonged tube placement can increase pain, infection risk, complication risk, and hospital stay. In this patient, early removal despite moderate output resulted in full resolution and no recurrence. Individualized, multidisciplinary decision-making—incorporating pleural fluid characteristics, patient comorbidities, and dynamic imaging assessment—can optimize outcomes and reduce unnecessary interventions in complex pleural infections. This abstract is funded by: None
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.
2026-04-12 | Effect of Glu235Ser on enzyme performance and in vitro characterization of human β-glucocerebrosidase in a Pichia pastoris.
Gaucher disease (GD) is the most common lysosomal storage disorder and is caused by inherited deficiency of β-glucocerebrosidase (GCase), resulting in glucocerebroside accumulation in multiple organs. Enzyme replacement therapy (ERT) is associated with complex and costly manufacturing processes, which has motivated the development of scalable expression systems. This study investigates recombinant production of human GCase using the Pichia pastoris GlycoSwitch® platform. The human β-glucocerebrosidase (gba) gene was cloned and expressed to generate both wild-type (WT) and mutant (Glu235Ser) GCase as functional glycoproteins. Both enzymes were purified and characterized using biochemical, kinetic, and computational analyses. The mutant exhibited higher catalytic efficiency, showing ~20 and ~10-fold increases in kcat/KM toward pNPG and 4-MUG, respectively, compared with WT. Both enzymes retained a similar optimal pH (8.0), while the mutant showed higher residual activity at elevated temperatures, retaining 50-60% activity with an optimal range of 60-70 °C. Structural modeling of the Glu235Ser variant suggested that catalysis might involve a His-Asp dyad mechanism. Modeling also indicated that the boat conformation of pNPG is both energetically favorable and catalytically preferred. In vitro assays indicated approximately 2-fold higher activity retention of the mutant under acidic and short-term plasma incubation conditions. In PMA-differentiated U937 macrophage-like cells, the mutant showed increased cellular uptake and prolonged intracellular activity compared to the wild-type enzyme; however, these effects may not be solely attributed to the mutation and may also be influenced by differences in glycosylation or other factors.
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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.
2025-05-30 | A Multiomic Network Approach to Uncover Disease Modifying Mechanisms of Inborn Errors of Metabolism.
For many inborn errors of metabolism (IEM) the understanding of disease mechanisms remains limited, in part explaining their unmet medical needs. The expressivity of IEM disease phenotypes is affected by disease-modifying factors, including rare and common polygenic variation. We hypothesize that we can identify these modulating pathways using molecular signatures of IEM in combination with multiomic data and gene regulatory networks generated from non-IEM animal and human populations. We tested this approach by identifying and subsequently validating glucocorticoid signaling as a candidate modifier of mitochondrial fatty acid oxidation disorders, and recapitulating complement signaling as a modifier of inflammation in Gaucher disease. Our work describes a novel approach that can overcome the rare disease-rare data dilemma and reveal new IEM pathophysiology and potential drug targets using multiomics data in seemingly healthy populations.
2025-05-28 | Developing nanobodies as allosteric molecular chaperones of glucocerebrosidase function.
The enzyme glucocerebrosidase (GCase) catalyses the hydrolysis of glucosylceramide to glucose and ceramide within lysosomes. Homozygous or compound heterozygous mutations in the GCase-encoding GBA1 gene cause the lysosomal storage disorder Gaucher disease, while heterozygous and homozygous mutations are the most frequent genetic risk factor for Parkinson's disease. These mutations commonly affect GCase stability, trafficking or activity. Here, we report the development and characterization of nanobodies (Nbs) targeting and acting as molecular chaperones for GCase. We identify several Nb families that bind with nanomolar affinity to GCase. Based on biochemical characterization, we group the Nbs in two classes: Nbs that improve the activity of the enzyme and Nbs that increase GCase stability in vitro. A selection of the most promising Nbs is shown to improve GCase function in cell models and positively impact the activity of the N370S mutant GCase. These results lay the foundation for the development of new therapeutic routes.
2024-12-13 | African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1.
Recently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (GBA1). This variant ( rs3115534 -G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups but is almost absent in European and Asian ancestry populations. GBA1 is a gene of high clinical and therapeutic interest. Damaging biallelic protein-coding variants cause Gaucher disease and monoallelic variants confer risk for PD and dementia with Lewy bodies, likely by reducing the function of glucocerebrosidase. Interestingly, the African ancestry-specific GBA1 risk variant is a noncoding variant, suggesting a different mechanism of action. Using full-length RNA transcript sequencing, we identified partial intron 8 expression in risk variant carriers (G) but not in nonvariant carriers (T). Antibodies targeting the N terminus of glucocerebrosidase showed that this intron-retained isoform is likely not protein coding and subsequent proteomics did not identify a shorter protein isoform, suggesting that the disease mechanism is RNA based. Clustered regularly interspaced short palindromic repeats editing of the reported index variant ( rs3115534 ) revealed that this is the sequence alteration responsible for driving the production of these transcripts containing intron 8. Follow-up analysis of this variant showed that it is in a key intronic branchpoint sequence and, therefore, has important implications in splicing and disease. In addition, when measuring glucocerebrosidase activity, we identified a dose-dependent reduction in risk variant carriers. Overall, we report the functional effect of a GBA1 noncoding risk variant, which acts by interfering with the splicing of functional GBA1 transcripts, resulting in reduced protein levels and reduced glucocerebrosidase activity. This understanding reveals a potential therapeutic target in an underserved and underrepresented population.
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Drug Discovery Landscape
3 orphan drug designations for Gaucher disease type 1, including 2 approved therapies.
3 orphan drug designations for Gaucher disease type 1, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Eliglustat Tartrate | small molecules | FDA | Amneal Pharmaceuticals LLC | |
eliglustat [CERDELGA] | small molecules | FDA | Approved | Genzyme Corporation |
Alglucerase injection [Ceredase] | proteins | FDA | Approved | Genzyme Corporation |
“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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