RARE DISEASE
Chronic visceral acid sphingomyelinase deficiency
Chronic visceral acid sphingomyelinase deficiency
Chronic visceral acid sphingomyelinase deficiency
Synonyms: Chronic visceral ASMD, NPD-B, Niemann-Pick disease type B
Synonyms: Chronic visceral ASMD, NPD-B, Niemann-Pick disease type B
Synonyms: Chronic visceral ASMD, NPD-B, Niemann-Pick disease type B
Drug discovery
0
drugs
With orphan designations
Overview
Chronic visceral acid sphingomyelinase deficiency (ASMD type B) is a rare autosomal recessive lysosomal storage disorder caused by SMPD1 gene mutations, leading to deficient acid sphingomyelinase activity and sphingomyelin accumulation in visceral organs. Key features include progressive hepatosplenomegaly, interstitial lung disease, dyslipidemia, thrombocytopenia, and osteopenia. Onset ranges from childhood to adulthood, with multisystem morbidity but no neurodegeneration. Diagnosis involves enzyme activity assays and genetic testing [1][2][5][6].
Burden
Major morbidities: Hepatosplenomegaly (80–92%), thrombocytopenia, progressive pulmonary dysfunction (↓DLCO), and liver failure [4][7][12].
Healthcare burden: 12–50% require outpatient/home healthcare; 16–22% experience educational/work limitations [4][7].
Mortality: Driven by respiratory/liver failure, with reduced life expectancy but survival into adulthood common [6][11][12].
Therapies
Supportive care: Management of hypersplenism, pulmonary infections, dyslipidemia, and osteoporosis; surveillance for liver fibrosis/respiratory decline [3][5][6].
Enzyme replacement therapy (ERT): Olipudase alfa (recombinant human acid sphingomyelinase) reduces sphingomyelin storage, improves lung/liver function, and normalizes lipid profiles in clinical trials [8][10][14].
Categories: rare endocrine diseases, rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare neurological diseases, rare respiratory diseases, rare transplant-related disorders
Research Papers
90 drug discovery papers about Chronic visceral acid sphingomyelinase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
90 drug discovery papers about Chronic visceral acid sphingomyelinase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-08-13 | Potential Mechanisms of Platelet Dysfunction and Bleeding in Acid Sphingomyelinase Deficiency.
Acid sphingomyelinase deficiency (ASMD) is an autosomal recessive lysosomal storage disorder caused by mutations in the SMPD1 gene, resulting in sphingomyelin accumulation. With a birth prevalence of 0.25-0.6 per 100,000, it is more prevalent in Ashkenazi Jewish and Middle Eastern populations. The disease features a clinical spectrum ranging from severe, early-onset neurodegeneration (infantile neurovisceral ASMD) to chronic, non-neurological visceral involvement (chronic visceral ASMD) and intermediate forms (chronic neurovisceral ASMD). The chronic visceral form is characterized by liver dysfunction, respiratory symptoms, and hepatosplenomegaly, which can lead to secondary thrombocytopenia. The majority of patients exhibit thrombocytopenia and/or mild bleeding manifestations, most commonly easy bruising and epistaxis, whereas clinically significant bleeding events, including gastrointestinal or variceal hemorrhage, occur less frequently. Systematic platelet-function studies in patients with ASMD are currently lacking. Evidence retrieved from biological models indicates that ASMD contributes to platelet dysfunction, including impaired secretion and thrombin generation, mediated by complex pathological mechanisms. These findings underscore the importance of hematological monitoring and further research in patients with this condition and could potentially offer new therapeutic possibilities.
2026-06-28 | Clinical Characteristics of 19 Patients With Acid Sphingomyelinase Deficiency: A Case Series From Multiple Centers in Argentina
ABSTRACT Acid sphingomyelinase deficiency (ASMD), historically known as Niemann‐Pick disease, is a rare and potentially fatal lysosomal storage disease caused by pathogenic variants in the sphingomyelin phosphodiesterase 1 ( SMPD1 ) gene, which encodes acid sphingomyelinase (ASM). Deficient ASM activity results in dysregulation of cellular membrane homeostasis and accumulation of sphingomyelin in multiple organs. ASMD spans a broad clinical spectrum, with symptoms varying at presentation depending on age at onset and degree and type of organ/systemic involvement. To describe the diagnostic experience and clinical manifestations of ASMD in Argentina, a national retrospective case series was conducted across seven centers in patients diagnosed between 1988 and 2022. Diagnosis was confirmed by reduced ASM activity, with SMPD1 sequencing performed when possible. Nineteen patients (8 females/11 males; 0–76 years) were identified: Type A (4, 21%), Type B (12, 63%), Type A/B (2, 11%), and one unknown. Average age at symptom onset was 3.9 years, and average age at diagnosis was 11.4 years, corresponding to a diagnostic delay of 7.5 years. All patients presented with hepatosplenomegaly. Anemia (79%), pulmonary involvement (79%), thrombocytopenia (79%), and osteopenia (56%) were also reported in a majority of patients. Two patients were initially misdiagnosed with Gaucher disease. This series highlights the variety of clinical presentations and substantial diagnostic delays associated with ASMD in Argentina. Increasing awareness across specialties is essential to improve disease recognition, reduce time to diagnosis, and prevent misdiagnosis.
2026-06-25 | Understanding Acid Sphingomyelinase Deficiency from a Clinical, Molecular, and Therapeutic Perspective
Acid sphingomyelinase deficiency (ASMD), also referred to as Niemann-Pick disease types A and B, is a rare lysosomal storage disorder. Mutations in the SMPD1 gene result in insufficient activity of the acid sphingomyelinase (ASM) enzyme, which causes acid sphingomyelinase deficiency (ASMD). This enzyme is necessary for the breakdown of sphingomyelin, a type of sphingolipid found in the membranes of animal cells, particularly in the outer leaflet of the plasma membrane. Without this enzyme, sphingomyelin cannot be broken down, leading to its accumulation in organs such as the liver, spleen, lungs and brain. Historically, acid sphingomyelinase deficiency (ASMD) has been classified as Niemann-Pick disease (NPD) types A and B. Type A is caused by severe deficiency in ASM leading to neurodegeneration and organ enlargement. This type typically results in death by the age of three. In contrast, type B results from partial ASM deficiency and patients typically survive but face various complications throughout their lives. Currently, treatment options for this disease are limited, although many therapeutic approaches are gradually developing. Early diagnosis and effective management can minimize the complications of this disease and increase life expectancy. So, this review aims to provide a comprehensive understanding of ASMD, including its epidemiology, pathogenesis, pathophysiology, clinical presentation and diagnostic approaches necessary for early detection.
2026-04-28 | Adults With Acid Sphingomyelinase Deficiency Have Sustained Improvements in Clinical Outcomes With up to 5 Years of Olipudase Alfa Enzyme Replacement Therapy: ASCEND Trial Final Results.
Acid sphingomyelinase deficiency (ASMD) is a rare debilitating lysosomal storage disease resulting in multisystemic disease manifestations, significant disease burden, and early mortality for some individuals. Enzyme replacement therapy (ERT) with olipudase alfa (Xenpozyme) is the first disease-specific treatment indicated for noncentral nervous system manifestations of ASMD in children and adults. During the 1-year primary analysis of the ASCEND placebo-controlled trial in 36 adults with ASMD, olipudase alfa treatment reduced sphingomyelin storage and was associated with clinically significant improvements relative to placebo in multiple endpoints. An open-label extension of the ASCEND trial followed 35 of 36 adults during olipudase alfa treatment for up to 5 years. Mean time on olipudase alfa was 4.2 ± 1.0 years; mean compliance was 90% ± 13%. During long-term olipudase alfa treatment, percent predicted diffusing capacity for carbon monoxide (DLCO) increased (mean 50.1% ± 10.8% at baseline vs. 66.5% ± 13.3% at final assessment; mean change from baseline of 35.9% ± 27.5% (p < 0.0001). Mean baseline spleen volume of 11.5 ± 4.6 multiples of normal (MN) decreased to 4.8 ± 2.1 MN at final assessment, mean change from baseline -57.5% ± 10.1% (p < 0.0001) and mean baseline liver volume (1.5 ± 0.4 MN) decreased to 0.95 ± 0.23 MN at final assessment, (mean change from baseline -36.8% ± 11.5%, p < 0.0001). Plasma lyso-sphingomyelin levels decreased by 72% from baseline to final assessment. Overall, improvements in clinical parameters occurred regardless of baseline severity. No new safety issues emerged during the trial extension and 98% of treatment emergent adverse events were mild/moderate. Improvements in visceral ASMD disease with olipudase alfa treatment will significantly impact the disease burden for those with this progressive multiorgan disorder.
2026-04-15 | Features of liver damage in Niemann — Pick disease type A, A/B and B (deficiency of acidic sphingomyelinase)
Background. Acid sphingomyelinase deficiency (Niemann – Pick disease) leads to the intracellular accumulation of sphingomyelin within the mononuclear phagocyte system, including liver, spleen, lungs and bone marrow. Liver involvement represents one of the earliest and persistent visceral manifestations of the disease. Foamy macrophages featuring prominent cytoplasmic vacuolation are generated within the liver. Intracellular accumulation of pathological substrates in hepatocytes results in several pathological changes, including inflammation and cytokine release, remodeling of the sinusoidal network, periportal and bridging fibrosis and progressive portal hypertension. Dyslipidemia, associated with Niemann – Pick disease, is characterised by elevated levels of various lipid fractions. Gradual lipid accumulation leads to the liver enlargement (hepatomegaly) and the development of hepatic steatosis. Hepatomegaly, biochemical abnormalities and progressive fibrosis significantly impair the patients' quality of life and adversely affect the prognosis of the disease. Objective. To analyze current data on the pathogenesis, clinical manifestations, morphological features, and treatment of liver damage in Niemann – Pick disease types A, A/B, and B. Materials and methods. A systematic review of publications from 2013-2025 on the clinical presentation, histopathology, and treatment of acid sphingomyelinase deficiency was conducted, including the impact of enzyme replacement therapy on liver pathology. Results. The liver is a key target organ in Niemann – Pick disease types A, A/B, and B. The spectrum of liver changes includes hepatomegaly, parenchymal infiltration with foamy macrophages, progressive fibrosis, cirrhosis, hepatic steatosis, and the possible development of portal hypertension and liver failure requiring transplantation. The severity of liver damage and the age at onset of changes depend on the disease phenotype. Liver failure, in addition to respiratory disease, is the leading cause of death in chronic forms of Niemann – Pick disease. Modern enzyme replacement therapy can reduce liver volume, improve biochemical parameters, and slow the progression of fibrosis. Conclusion. Early diagnosis and pathogenetic therapy are key to slowing the progression of liver disease in acid sphingomyelinase deficiency.
cell therapies
2024-07-09 | Course of Niemann – Pick disease type A/B in the context of hematopoietic stem cell transplantation
Niemann – Pick disease type A/B (NPAB) is a rare severe inherited disease from the group of accumulation diseases with a defect in the acid sphingomyelinase gene (Niemann-Pick disease types B, A/B) (ASMD). Symptoms of damage to the nervous system and internal organs manifest in infancy, leading to disability, fatalities in childhood. NPAB is so far incurable. Optimal management of the disease requires a multidisciplinary team of physicians, specialists. The basis of therapy is the elimination of existing/forming complications, symptomatic treatment. Enzyme replacement therapy as a means of modifying the course of this disease is expected to slow down the progression of pathologic manifestations of the disease not related to the central nervous system lesions. Single cases of hematopoietic stem cell transplantation (HSCT) have been described in the treatment of ASMD, which is one of the new methods aimed at normalizing the level of acid sphingomyelinase, blood parameters, as well as reducing the severity of pathological visceral manifestations. However, the development of complications during HSCT, absence of positive therapeutic effect in severe CNS lesions does not allow to widely implement this method. Taking into account the contradictory data on the efficacy of HSCT in ASMD, further clinical studies are required. Analysis of 2 clinical cases of NPAB in children from the same family allowed us to reveal differences in the course and outcomes of the disease at verification of the diagnosis at birth followed by HSCT. Difficulties in diagnosing this extremely rare pathology, which requires a multidisciplinary approach, justify the need to improve methods of early diagnosis, including the organization of genetic risk determination, introduction of prenatal genetic testing before pregnancy.
2021-10-14 | Bilateral Cystic Bronchiectasis as Novel Phenotype of Niemann-Pick Disease Type B Successfully Treated With Double Lung Transplantation.
Niemann-Pick Disease type B (NPDB) is a rare autosomal recessive disease belonging to the family of lysosomal storage disorders. NPDB is caused by mutations of sphingomyelin phosphodiesterase 1 gene (SMPD1) and is characterized by hepatosplenomegaly, interstitial lung disease, recurrent pulmonary infections, and neurologic disorders. Bronchiectasis are atypical. Until now, only three cases of lung transplantation for severe respiratory impairment have been reported. We describe a case of NPDB that was diagnosed after lung transplantation for cystic bronchiectasis. In 2016, a 31-year-old woman who was experiencing hypoxemic respiratory failure and recurrent pulmonary infections due to cystic bronchiectasis received a double-lung-transplantation. Histopathologic study on removed lungs revealed clusters of CD68 foamy lipid-laden macrophages with concentric and palisade arrangement, compatible with the diagnosis of NPDB, which was confirmed after SMPD1 genetic sequencing. Twenty-three months after transplantation, allograft function is stable (FEV1 was 100% of best-FEV1). The singularity of this case lies in the presence of bronchiectasis, which is an unprecedently described phenotype of NPDB. This finding was accompanied by the detection of a novel SMPD1 mutation (p.Ala46=) of uncertain meaning.
2020-03-11 | Generation of an induced pluripotent stem cell line (TRNDi004-I) from a Niemann-Pick disease type B patient carrying a heterozygous mutation of p.L43_A44delLA in the SMPD1 gene.
Niemann-Pick disease type B (NPB) is a rare autosomal recessive lysosomal storage disease caused by mutations in the SMPD1 gene, which encodes for acid sphingomyelinase. A human induced pluripotent stem cell (iPSC) line was generated from dermal fibroblasts of a 1-year old male patient with NPB that has a heterozygous mutation of a p.L43_A44delLA of SMPD1 using non-integrating Sendai virus technique. This iPSC line offers a useful resource to study the disease pathophysiology and as a cell-based model for drug development to treat NPB.
2019-06-16 | Pulmonary Type B Niemann-Pick Disease Successfully Treated with Lung Transplantation
Niemann-Pick Disease (NPD) type B is a rare autosomal recessive disease characterised by hepatosplenomegaly and pulmonary disease, highlighted by preserved volumes and diminished diffusion capacity of the lung for carbon monoxide (DLCO) on pulmonary function tests (PFTs). There is no current accepted treatment for the disease. We present a case of a successful bilateral lung transplant in a patient with a DLCO of 14%, and significant pulmonary changes attributable to NPD type B on computed tomography (CT) chest, and both microscopic and macroscopic assessment of the lung explant. To the author's knowledge this is only the third case of lung transplantation in a patient with NPD type B and is one of two current living patients post lung transplantation for NPD type B.A 64-year-old male patient underwent bilateral lung transplantation for NPD type B. Preoperative PFTs demonstrated preserved volumes with significantly decreased DLCO, with imaging showing a diffuse reticular interstitial pattern, typical of chronic fibrotic lung disease. The patient suffered from primary graft dysfunction type 3 in the postoperative period as well as rejection managed with methylprednisolone and intravenous immunoglobulin. The patient improved steadily and was discharged 80 days post-transplantation.This case is only the third reported case of lung transplantation in a patient with NPD type B and the second case of a patient with NPD type B currently living post-transplantation, being at postoperative day (POD) 267 at the time of manuscript drafting. It demonstrates that lung transplantation, although hazardous, is a viable strategy for treatment in patients with NPD type B who have significant pulmonary involvement.
2019-05-16 | Respiratory impairment in Niemann-Pick B disease: Two case reports and review for the pulmonologist
Acid sphingomyelinase deficiency (ASMD), also called Niemann-Pick disease, is a storage disorder with pulmonary involvement but few respiratory symptoms in adults. However, the disease may evolve towards clinically relevant respiratory symptoms with referral to the pulmonologist for management and care. Based on two case reports illustrating respiratory impairment, the aim of this work was to review clinical features, diagnosis, respiratory prognostic and therapeutics for the pulmonologist. Overall, storage disorder should be suspected in the presence of hepatosplenomegaly and interstitial lung disease. Concomitant thrombopenia or hyperlipidemia should also draw attention. Following recent consensus guidelines, diagnosis is based on enzyme assay for ASM activity in blood, with subsequent gene sequencing once the biochemical diagnosis has been confirmed. Disease is slowly progressive and the main causes of death are respiratory and liver failure. Presence of emphysema lesions or worsening of respiratory symptoms should call for the intensification of treatment. Though enzyme replacement therapy is a promising way of development, lung transplantation might be considered for these patients in the absence of contraindication.
gene therapies
2025-10-12 | Current and Emerging Treatments for Acid Sphingomyelinase Deficiency.
Acid sphingomyelinase deficiency is an ultra-rare disease characterised by generalised storage of sphingomyelin, caused by deficiency of the lysosomal enzyme acid sphingomyelinase, owing to the presence of biallelic pathogenic variants in the SMPD1 gene. The main disease manifestations are in the liver, spleen, lung and bone - with some patients having also involvement of the central nervous system. Patients show variable degrees of anaemia, thrombocytopenia and lipid abnormalities, among other findings. Clinically, acid sphingomyelinase deficiency spans from an acute neurovisceral form, with neurological involvement and early death (type A), to a chronic visceral disease, with no or minimal neurological manifestations (type B). An intermediate form, with chronic neurovisceral involvement, is presented by some patients (type A/B). Diagnosis involves the measurement of biomarkers, an assay of enzyme activity and genetic testing. Until a few years ago, treatment was mainly dependent on symptomatic management and bone marrow or solid organ (liver and/or lung) transplantation. In 2022, a specific enzyme replacement therapy with olipudase alfa was approved, and the results available indicate that it changed the therapeutic landscape for patients with acid sphingomyelinase deficiency type B and A/B. Research is being developed to address the needs of patients with acid sphingomyelinase deficiency type A, with gene therapy remaining as a promising approach.
2024-05-07 | Overview of clinical, molecular, and therapeutic features of Niemann–Pick disease (types A, B, and C): Focus on therapeutic approaches
Abstract Niemann–Pick disease (NPD) is another type of metabolic disorder that is classified as lysosomal storage diseases (LSDs). The main cause of the disease is mutation in the SMPD1 (type A and B) or NPC1 or NPC2 (type C) genes, which lead to the accumulation of lipid substrates in the lysosomes of the liver, brain, spleen, lung, and bone marrow cells. This is followed by multiple cell damage, dysfunction of lysosomes, and finally dysfunction of body organs. So far, about 346, 575, and 30 mutations have been reported in SMPD1 , NPC1 , and NPC2 genes, respectively. Depending on the type of mutation and the clinical symptoms of the disease, the treatment will be different. The general aim of the current study is to review the clinical and molecular characteristics of patients with NPD and study various treatment methods for this disease with a focus on gene therapy approaches.
2013-08-22 | Cholesterol trapping in Niemann-Pick disease type B fibroblasts can be relieved by expressing the phosphotyrosine binding domain of GULP.
Impairment of acid sphingomyelinase (SMase) results in accumulation of sphingomyelin (SM) and cholesterol in late endosomes, the hallmarks of a lysosomal storage disease. We describe cellular lipid metabolism in fibroblasts from two patients with novel compound heterozygote mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene manifesting as Niemann-Pick disease type B (NPB) and demonstrate mechanisms to overcome the storage defect. Using biochemical assays and confocal microscopy, we provide evidence that accumulated lysosomal SM and cholesterol can be released by different treatments. Defective SMase activity in these fibroblasts results in a 2.5-fold increased cellular mass of SM and cholesterol, increased de novo endogenous cholesterol synthesis, and decreased cholesterol esterification, demonstrating impaired intracellular cholesterol homeostasis. Depletion of exogenous addition of cholesterol for 24 hours or addition of the cholesterol acceptor apolipoprotein A-I are sufficient to restore normal homeostatic responses. In an effort to correct the lysosomal storage phenotype of NPB, we infected the fibroblasts with a lentivirus expressing the phosphotyrosine binding domain of the adapter protein GULP (PTB-GULP). We have previously shown that expression of PTB-GULP in Chinese hamster ovary cells promotes intracellular cholesterol trafficking and ABCA1-mediated cholesterol efflux. We find that expression of PTB-GULP in NPB fibroblasts results in increased ABCA1 expression, increased cellular cholesterol efflux and lysosomal cholesterol redistribution, independent of the impaired SMase and cholesterol presence. We provide extensive functional characterization of a novel compound heterozygote mutation and provide a novel functional mechanism to overcome lysosomal storage disease defects.
1992-04-15 | Retroviral-mediated transfer of the human acid sphingomyelinase cDNA: correction of the metabolic defect in cultured Niemann-Pick disease cells.
Types A and B Niemann-Pick disease (NPD) result from inherited deficiencies of the lysosomal hydrolase, acid sphingomyelinase (ASM; sphingomyelin cholinephosphohydrolase, EC 3.1.4.12). To evaluate the feasibility of somatic gene therapy for the treatment of these disorders, retroviral-mediated gene transfer was used to introduce the full-length ASM cDNA into cultured fibroblasts from two unrelated type A NPD patients. The ASM activities in these cells were less than 4% of mean normal levels, and, consequently, they accumulated approximately 3-fold elevated levels of sphingomyelin. After retroviral-mediated transfer of the ASM cDNA, ASM activities in the NPD cells increased to levels up to 16-fold those found in normal fibroblasts. In addition, the sphingomyelin content was reduced to normal levels, indicating that the vector-encoded enzyme was properly targeted to lysosomes, where it was enzymatically active and able to degrade the accumulated substrate. In situ cell-loading studies also were undertaken to evaluate the effects of retroviral-mediated gene transfer on the pathology of NPD fibroblasts. When a pyrene derivative of sphingomyelin was introduced into the lysosomes of cultured fibroblasts from a type A NPD patient by using apolipoprotein E-mediated endocytosis, only approximately 6% of the delivered substrate was degraded. In contrast, normal cells and NPD cells transduced (i.e., "corrected") by retroviral-mediated gene transfer could degrade approximately 80% of the delivered sphingomyelin. These results provided further evidence that retroviral-mediated gene transfer may be used to correct the pathology of NPD cells. Cell-loading studies were also used to develop a selection system for discriminating between NPD cells and those transduced by retroviral-mediated gene transfer. This selection scheme was based on the fluorescence emission of intact NPD cells, which, when loaded with pyrene-labeled sphingomyelin, was 3- to 5-fold that of normal or transduced cells. As a consequence, the NPD and transduced cells could be efficiently sorted by flow cytometry with a fluorescence-activated cell sorter. In addition, the NPD cells could be selectively killed by photosensitization after irradiation with a long-wavelength UV light. These results should permit direct selection of ASM-expressing cells after retroviral-mediated gene transfer without the need to preselect for a cotransferred marker gene.
small molecules
2026-07-03 | The Sphingolipid Balance and Endothelial Dysfunction in Lysosomal Storage Diseases: Shared Mechanisms in Gaucher, Niemann–Pick and Fabry Disease
Endothelial dysfunction underlies many cardiovascular and metabolic diseases. Lysosomal storage disorders, particularly sphingolipidoses, cause intracellular accumulation of specific sphingolipids due to inherited enzyme defects. This review focuses on Gaucher, Niemann–Pick (types A, B, A/B) and Fabry diseases, selected because they exhibit clinically significant cardiovascular manifestations and each accumulates a distinct sphingolipid—glucocerebroside, sphingomyelin, or globotriaosylceramide—allowing comparative analysis of how different metabolic defects converge on similar endothelial phenotypes. We summarize current knowledge on how substrate accumulation disrupts the ceramide/sphingosine-1-phosphate (S1P) rheostat, affecting NO synthase, vascular permeability, inflammation, angiogenesis, autophagy and cell death. Common and disease-specific changes in endothelial morphology and barrier function are discussed. Importantly, direct experimental evidence for endothelial involvement in Gaucher and Niemann–Pick diseases remains scarce; most mechanistic insights derive from non-endothelial cell models, highlighting a significant gap that underscores the need for targeted endothelial studies. Deficiencies of GBA1, SMPD1, and GLA each modulate S1P and ceramide production through distinct pathways, yet all three conditions share similar functional endothelial alterations driven by disrupted sphingolipid homeostasis. Understanding these common mechanisms opens new perspectives for diagnostic biomarkers and therapeutic strategies aimed at restoring sphingolipid balance in the endothelium, though further research is required to validate these findings in endothelial-specific contexts.
2026-04-26 | Curcumin controls lysosomal acidification and exocytosis to ameliorate lysosomal cholesterol accumulation in Niemann–Pick type C disease
Abstract Background and Purpose Niemann–Pick type C disease (NPCD) is a rare and fatal lysosomal storage disorder. There are limited therapies for NPCD, although multiple small‐molecule compounds have shown therapeutic potential for NPCD. Curcumin (CUR), a polyphenolic compound enriched in turmeric, has cholesterol‐lowering effects via regulating intestinal cholesterol absorption and liver cholesterol synthesis. CUR normalises sphingolipid trafficking and stimulates exosome/microvesicle release, increases cytosolic Ca 2+ levels, and enhances lysosomal activation via mTOR suppression and TFEB activation. How CUR specifically targets lysosomal cholesterol has not been fully clarified. Experimental Approach Effects of curcumin on lysosomal cholesterol accumulation were evaluated in NPC1 cell models. Filipin staining, immunofluorescence, surface LAMP1 and NAGase activity and Cathepsin B activity were investigated to evaluate lysosomal cholesterol, TFEB translocation, lysosomal exocytosis and hydrolytic activity. Lysosomal acidification was determined by Lysotracker Red, Oregon Green, and sfGFP/mCherry transfection. CRISPR/Cas9 and siRNA interference were used to investigate the role of TFEB/TFE3 and TRPML1 in curcumin‐induced cholesterol reduction. Key Results CUR alleviates lysosomal cholesterol accumulation in NPC1 cells in a TFEB‐ and TFE3‐dependent manner. CUR enhanced lysosomal acidity and promoted calcium‐dependent lysosomal exocytosis, which contributed to CUR‐mediated lysosomal cholesterol clearance. The combination of CUR with specific agonists (ML‐SAs) of MCOLN1/TRPML1, a lysosomal cation channel required for lysosomal exocytosis, improved lysosomal cholesterol clearance. Conclusion and Implications CUR reduces lysosomal cholesterol accumulation in NPC1 cells by activating TFEB/TFE3 pathways and promoting Ca 2+ ‐ and TRPML1‐dependent lysosomal exocytosis. These findings support curcumin and its analogues as potential therapeutics for NPCD and other diseases of lysosomal storage.
2026-04-10 | Zuclopenthixol inhibits residual activity of acid sphingomyelinase in Niemann pick disease type B: a case report with in vitro validation.
Niemann-Pick disease type B (NPD-B) is a rare lysosomal storage disorder characterized by residual activity of acid sphingomyelinase (ASM). While functional inhibitors of ASM (FIASMAs) are widely prescribed as psychotropic medications, they may pose a particular risk to patients with NPD-B by further reducing the already impaired enzymatic function. Here, we report the case of a 20-year-old male with genetically confirmed NPD-B who experienced rapid clinical deterioration following the administration of zuclopenthixol, a drug not previously associated with FIASMA activity. Within 48 hours of treatment initiation, the patient developed profound lethargy and markedly elevated creatine kinase (CK) levels of up to 22,000 U/L, consistent with rhabdomyolysis. Symptoms resolved quickly after discontinuation of zuclopenthixol. In vitro experiments using a radioactive [1 4 C]-sphingomyelin assay in Jurkat cells demonstrated that zuclopenthixol dose-dependently inhibited ASM activity by up to 71.5%. Zuclopenthixol had not previously been recognized as a FIASMA and might therefore have been considered a rational choice for treating patients with NPD-B. Our findings challenge this assumption by identifying zuclopenthixol as a potent inhibitor of ASM activity. This novel insight is of high clinical relevance, given the frequent use of antipsychotics in the management of neuropsychiatric symptoms in lysosomal storage disorders. We propose that zuclopenthixol and other potential FIASMAs be carefully re-evaluated for use in this vulnerable patient population.
2026-01-01 | Metabolic improvement in patients with acid sphingomyelinase deficiency following intravenous trehalose administration: an untargeted pharmacometabolomic study
Abstract Background Acid sphingomyelinase deficiency (ASMD) A and B, historically known as Niemann-Pick (NP) types A (NPA) and B (NPB), are life-threatening and rare inherited lysosomal storage disorders, caused by a deficiency in the acid sphingomyelinase enzyme activity. The negative outcome of this deficiency is the sphingomyelin (SM) accumulation in different organs and tissues. Trehalose is a natural disaccharide with neuroprotective and autophagy-inducing abilities that has recently been shown to improve clinical and biochemical features of patients with ASMD A/B. We previously showed that trehalose can reduce the serum levels of sphingomyelins and improve disease symptoms caused by lipid accumulation in ASMD A/B patients. Aim The aim of this study was to investigate the serum metabolome changes in five patients with ASMD A/B, who received 15 g/week of trehalose intravenously for three months, using an untargeted gas chromatography-mass spectrometry (GC-MS) method. Methods and materials GC-MS technique was used to assess the serum metabolic profile of patients with ASMD A/B. MSDIAL was used for data processing, and multivariate data analysis including Principal Component Analysis (PCA), and Orthogonal projections to latent structures discriminant analysis (OPLS-DA) algorithms were carried out using SIMCA. Results OPLS-DA model revealed significant changes in several serum metabolites including phosphate (P = 0.0019), sorbitol (P = 0.00009), myoinositol (P = 0.02), threonine (P = 0.01), lactic acid (P = 0.0001), 1-monopalmitin (P = 0.01), threitol (P = 0.002), ribitol (P = 0.008), and D-ribose (P = 0.007) following trehalose treatment. Conclusion The findings revealed that the beneficial effects of trehalose in patients with ASMD might be mediated by metabolic alterations. A clear shift in glucose metabolism in favor of less fatty acid production together with facilitating the breakdown of sphingomyelins is involved in the observed protective activity.
2025-02-07 | Short-Term Acid Sphingomyelinase Deficiency Exerts Proinflammatory and Antiapoptotic Effects during LPS-induced Lung Injury in Mice
Lysosomal acid sphingomyelinase (ASM; SMPD1) deficiency causes Niemann-Pick disease that, in type B, manifests with interstitial lung disease and susceptibility to infections. Constitutional Smpd1 (Smpd1-/- mouse) deletion causes lung inflammation with foamy dysfunctional macrophages but is protective against acute lung injury. It is unknown whether these manifestations are a result of progressive accumulation of sphingomyelin, decreased ceramide, or compensatory alterations in sphingolipid metabolism. We developed a conditional knockout mouse, CAGG-CreERTM × Smpd1fl/fl, induced by tamoxifen (5 wk), with decreased Smpd1 expression (by 75%) and ASM activity (by up to 40%). We investigated how brief postdevelopmental ASM insufficiency affects lung sphingolipids and pathology, including after LPS-induced injury. Compared with control animals, Smpd1fl/fl mice exhibited modest sphingomyelin elevation with lower palmitoyl/lignoceroyl ceramide (C16/C24) ratios and increased de novo sphingolipid synthesis and sphingosine-1-phosphate concentrations. At 3 days after LPS instillation (20 μg), control mice had increased lung (neutrophilic and monocytic) inflammation and apoptosis; Smpd1fl/fl mice showed more exuberant inflammation, but had significantly reduced apoptosis, particularly in endothelial cells. During repair phase (6-9 d), Smpd1fl/fl lungs had increased cell proliferation with reduced accumulation of autophagosome-tagging p62/SQSTM1. These results indicate that before developing lysosomal lipid storage, ASM insufficiency inhibits stress-induced lung apoptosis and promotes compensatory sphingolipid changes that favor exuberant inflammatory responses to LPS. Overall, ASM inhibition limits lung vascular injury and may stimulate repair after inflammatory insults. These results provide novel insights into the function of ASM in the lung, which are relevant to understanding the pathogenesis and complications of Niemann-Pick disease and the role of distinct sphingolipid metabolites in lung injury and repair.
proteins
2026-08-13 | Potential Mechanisms of Platelet Dysfunction and Bleeding in Acid Sphingomyelinase Deficiency.
Acid sphingomyelinase deficiency (ASMD) is an autosomal recessive lysosomal storage disorder caused by mutations in the SMPD1 gene, resulting in sphingomyelin accumulation. With a birth prevalence of 0.25-0.6 per 100,000, it is more prevalent in Ashkenazi Jewish and Middle Eastern populations. The disease features a clinical spectrum ranging from severe, early-onset neurodegeneration (infantile neurovisceral ASMD) to chronic, non-neurological visceral involvement (chronic visceral ASMD) and intermediate forms (chronic neurovisceral ASMD). The chronic visceral form is characterized by liver dysfunction, respiratory symptoms, and hepatosplenomegaly, which can lead to secondary thrombocytopenia. The majority of patients exhibit thrombocytopenia and/or mild bleeding manifestations, most commonly easy bruising and epistaxis, whereas clinically significant bleeding events, including gastrointestinal or variceal hemorrhage, occur less frequently. Systematic platelet-function studies in patients with ASMD are currently lacking. Evidence retrieved from biological models indicates that ASMD contributes to platelet dysfunction, including impaired secretion and thrombin generation, mediated by complex pathological mechanisms. These findings underscore the importance of hematological monitoring and further research in patients with this condition and could potentially offer new therapeutic possibilities.
2026-06-28 | Clinical Characteristics of 19 Patients With Acid Sphingomyelinase Deficiency: A Case Series From Multiple Centers in Argentina
ABSTRACT Acid sphingomyelinase deficiency (ASMD), historically known as Niemann‐Pick disease, is a rare and potentially fatal lysosomal storage disease caused by pathogenic variants in the sphingomyelin phosphodiesterase 1 ( SMPD1 ) gene, which encodes acid sphingomyelinase (ASM). Deficient ASM activity results in dysregulation of cellular membrane homeostasis and accumulation of sphingomyelin in multiple organs. ASMD spans a broad clinical spectrum, with symptoms varying at presentation depending on age at onset and degree and type of organ/systemic involvement. To describe the diagnostic experience and clinical manifestations of ASMD in Argentina, a national retrospective case series was conducted across seven centers in patients diagnosed between 1988 and 2022. Diagnosis was confirmed by reduced ASM activity, with SMPD1 sequencing performed when possible. Nineteen patients (8 females/11 males; 0–76 years) were identified: Type A (4, 21%), Type B (12, 63%), Type A/B (2, 11%), and one unknown. Average age at symptom onset was 3.9 years, and average age at diagnosis was 11.4 years, corresponding to a diagnostic delay of 7.5 years. All patients presented with hepatosplenomegaly. Anemia (79%), pulmonary involvement (79%), thrombocytopenia (79%), and osteopenia (56%) were also reported in a majority of patients. Two patients were initially misdiagnosed with Gaucher disease. This series highlights the variety of clinical presentations and substantial diagnostic delays associated with ASMD in Argentina. Increasing awareness across specialties is essential to improve disease recognition, reduce time to diagnosis, and prevent misdiagnosis.
2026-06-25 | Understanding Acid Sphingomyelinase Deficiency from a Clinical, Molecular, and Therapeutic Perspective
Acid sphingomyelinase deficiency (ASMD), also referred to as Niemann-Pick disease types A and B, is a rare lysosomal storage disorder. Mutations in the SMPD1 gene result in insufficient activity of the acid sphingomyelinase (ASM) enzyme, which causes acid sphingomyelinase deficiency (ASMD). This enzyme is necessary for the breakdown of sphingomyelin, a type of sphingolipid found in the membranes of animal cells, particularly in the outer leaflet of the plasma membrane. Without this enzyme, sphingomyelin cannot be broken down, leading to its accumulation in organs such as the liver, spleen, lungs and brain. Historically, acid sphingomyelinase deficiency (ASMD) has been classified as Niemann-Pick disease (NPD) types A and B. Type A is caused by severe deficiency in ASM leading to neurodegeneration and organ enlargement. This type typically results in death by the age of three. In contrast, type B results from partial ASM deficiency and patients typically survive but face various complications throughout their lives. Currently, treatment options for this disease are limited, although many therapeutic approaches are gradually developing. Early diagnosis and effective management can minimize the complications of this disease and increase life expectancy. So, this review aims to provide a comprehensive understanding of ASMD, including its epidemiology, pathogenesis, pathophysiology, clinical presentation and diagnostic approaches necessary for early detection.
2026-04-28 | Adults With Acid Sphingomyelinase Deficiency Have Sustained Improvements in Clinical Outcomes With up to 5 Years of Olipudase Alfa Enzyme Replacement Therapy: ASCEND Trial Final Results.
Acid sphingomyelinase deficiency (ASMD) is a rare debilitating lysosomal storage disease resulting in multisystemic disease manifestations, significant disease burden, and early mortality for some individuals. Enzyme replacement therapy (ERT) with olipudase alfa (Xenpozyme) is the first disease-specific treatment indicated for noncentral nervous system manifestations of ASMD in children and adults. During the 1-year primary analysis of the ASCEND placebo-controlled trial in 36 adults with ASMD, olipudase alfa treatment reduced sphingomyelin storage and was associated with clinically significant improvements relative to placebo in multiple endpoints. An open-label extension of the ASCEND trial followed 35 of 36 adults during olipudase alfa treatment for up to 5 years. Mean time on olipudase alfa was 4.2 ± 1.0 years; mean compliance was 90% ± 13%. During long-term olipudase alfa treatment, percent predicted diffusing capacity for carbon monoxide (DLCO) increased (mean 50.1% ± 10.8% at baseline vs. 66.5% ± 13.3% at final assessment; mean change from baseline of 35.9% ± 27.5% (p < 0.0001). Mean baseline spleen volume of 11.5 ± 4.6 multiples of normal (MN) decreased to 4.8 ± 2.1 MN at final assessment, mean change from baseline -57.5% ± 10.1% (p < 0.0001) and mean baseline liver volume (1.5 ± 0.4 MN) decreased to 0.95 ± 0.23 MN at final assessment, (mean change from baseline -36.8% ± 11.5%, p < 0.0001). Plasma lyso-sphingomyelin levels decreased by 72% from baseline to final assessment. Overall, improvements in clinical parameters occurred regardless of baseline severity. No new safety issues emerged during the trial extension and 98% of treatment emergent adverse events were mild/moderate. Improvements in visceral ASMD disease with olipudase alfa treatment will significantly impact the disease burden for those with this progressive multiorgan disorder.
2026-04-15 | Features of liver damage in Niemann — Pick disease type A, A/B and B (deficiency of acidic sphingomyelinase)
Background. Acid sphingomyelinase deficiency (Niemann – Pick disease) leads to the intracellular accumulation of sphingomyelin within the mononuclear phagocyte system, including liver, spleen, lungs and bone marrow. Liver involvement represents one of the earliest and persistent visceral manifestations of the disease. Foamy macrophages featuring prominent cytoplasmic vacuolation are generated within the liver. Intracellular accumulation of pathological substrates in hepatocytes results in several pathological changes, including inflammation and cytokine release, remodeling of the sinusoidal network, periportal and bridging fibrosis and progressive portal hypertension. Dyslipidemia, associated with Niemann – Pick disease, is characterised by elevated levels of various lipid fractions. Gradual lipid accumulation leads to the liver enlargement (hepatomegaly) and the development of hepatic steatosis. Hepatomegaly, biochemical abnormalities and progressive fibrosis significantly impair the patients' quality of life and adversely affect the prognosis of the disease. Objective. To analyze current data on the pathogenesis, clinical manifestations, morphological features, and treatment of liver damage in Niemann – Pick disease types A, A/B, and B. Materials and methods. A systematic review of publications from 2013-2025 on the clinical presentation, histopathology, and treatment of acid sphingomyelinase deficiency was conducted, including the impact of enzyme replacement therapy on liver pathology. Results. The liver is a key target organ in Niemann – Pick disease types A, A/B, and B. The spectrum of liver changes includes hepatomegaly, parenchymal infiltration with foamy macrophages, progressive fibrosis, cirrhosis, hepatic steatosis, and the possible development of portal hypertension and liver failure requiring transplantation. The severity of liver damage and the age at onset of changes depend on the disease phenotype. Liver failure, in addition to respiratory disease, is the leading cause of death in chronic forms of Niemann – Pick disease. Modern enzyme replacement therapy can reduce liver volume, improve biochemical parameters, and slow the progression of fibrosis. Conclusion. Early diagnosis and pathogenetic therapy are key to slowing the progression of liver disease in acid sphingomyelinase deficiency.
cell therapies
2024-07-09 | Course of Niemann – Pick disease type A/B in the context of hematopoietic stem cell transplantation
Niemann – Pick disease type A/B (NPAB) is a rare severe inherited disease from the group of accumulation diseases with a defect in the acid sphingomyelinase gene (Niemann-Pick disease types B, A/B) (ASMD). Symptoms of damage to the nervous system and internal organs manifest in infancy, leading to disability, fatalities in childhood. NPAB is so far incurable. Optimal management of the disease requires a multidisciplinary team of physicians, specialists. The basis of therapy is the elimination of existing/forming complications, symptomatic treatment. Enzyme replacement therapy as a means of modifying the course of this disease is expected to slow down the progression of pathologic manifestations of the disease not related to the central nervous system lesions. Single cases of hematopoietic stem cell transplantation (HSCT) have been described in the treatment of ASMD, which is one of the new methods aimed at normalizing the level of acid sphingomyelinase, blood parameters, as well as reducing the severity of pathological visceral manifestations. However, the development of complications during HSCT, absence of positive therapeutic effect in severe CNS lesions does not allow to widely implement this method. Taking into account the contradictory data on the efficacy of HSCT in ASMD, further clinical studies are required. Analysis of 2 clinical cases of NPAB in children from the same family allowed us to reveal differences in the course and outcomes of the disease at verification of the diagnosis at birth followed by HSCT. Difficulties in diagnosing this extremely rare pathology, which requires a multidisciplinary approach, justify the need to improve methods of early diagnosis, including the organization of genetic risk determination, introduction of prenatal genetic testing before pregnancy.
2021-10-14 | Bilateral Cystic Bronchiectasis as Novel Phenotype of Niemann-Pick Disease Type B Successfully Treated With Double Lung Transplantation.
Niemann-Pick Disease type B (NPDB) is a rare autosomal recessive disease belonging to the family of lysosomal storage disorders. NPDB is caused by mutations of sphingomyelin phosphodiesterase 1 gene (SMPD1) and is characterized by hepatosplenomegaly, interstitial lung disease, recurrent pulmonary infections, and neurologic disorders. Bronchiectasis are atypical. Until now, only three cases of lung transplantation for severe respiratory impairment have been reported. We describe a case of NPDB that was diagnosed after lung transplantation for cystic bronchiectasis. In 2016, a 31-year-old woman who was experiencing hypoxemic respiratory failure and recurrent pulmonary infections due to cystic bronchiectasis received a double-lung-transplantation. Histopathologic study on removed lungs revealed clusters of CD68 foamy lipid-laden macrophages with concentric and palisade arrangement, compatible with the diagnosis of NPDB, which was confirmed after SMPD1 genetic sequencing. Twenty-three months after transplantation, allograft function is stable (FEV1 was 100% of best-FEV1). The singularity of this case lies in the presence of bronchiectasis, which is an unprecedently described phenotype of NPDB. This finding was accompanied by the detection of a novel SMPD1 mutation (p.Ala46=) of uncertain meaning.
2020-03-11 | Generation of an induced pluripotent stem cell line (TRNDi004-I) from a Niemann-Pick disease type B patient carrying a heterozygous mutation of p.L43_A44delLA in the SMPD1 gene.
Niemann-Pick disease type B (NPB) is a rare autosomal recessive lysosomal storage disease caused by mutations in the SMPD1 gene, which encodes for acid sphingomyelinase. A human induced pluripotent stem cell (iPSC) line was generated from dermal fibroblasts of a 1-year old male patient with NPB that has a heterozygous mutation of a p.L43_A44delLA of SMPD1 using non-integrating Sendai virus technique. This iPSC line offers a useful resource to study the disease pathophysiology and as a cell-based model for drug development to treat NPB.
2019-06-16 | Pulmonary Type B Niemann-Pick Disease Successfully Treated with Lung Transplantation
Niemann-Pick Disease (NPD) type B is a rare autosomal recessive disease characterised by hepatosplenomegaly and pulmonary disease, highlighted by preserved volumes and diminished diffusion capacity of the lung for carbon monoxide (DLCO) on pulmonary function tests (PFTs). There is no current accepted treatment for the disease. We present a case of a successful bilateral lung transplant in a patient with a DLCO of 14%, and significant pulmonary changes attributable to NPD type B on computed tomography (CT) chest, and both microscopic and macroscopic assessment of the lung explant. To the author's knowledge this is only the third case of lung transplantation in a patient with NPD type B and is one of two current living patients post lung transplantation for NPD type B.A 64-year-old male patient underwent bilateral lung transplantation for NPD type B. Preoperative PFTs demonstrated preserved volumes with significantly decreased DLCO, with imaging showing a diffuse reticular interstitial pattern, typical of chronic fibrotic lung disease. The patient suffered from primary graft dysfunction type 3 in the postoperative period as well as rejection managed with methylprednisolone and intravenous immunoglobulin. The patient improved steadily and was discharged 80 days post-transplantation.This case is only the third reported case of lung transplantation in a patient with NPD type B and the second case of a patient with NPD type B currently living post-transplantation, being at postoperative day (POD) 267 at the time of manuscript drafting. It demonstrates that lung transplantation, although hazardous, is a viable strategy for treatment in patients with NPD type B who have significant pulmonary involvement.
2019-05-16 | Respiratory impairment in Niemann-Pick B disease: Two case reports and review for the pulmonologist
Acid sphingomyelinase deficiency (ASMD), also called Niemann-Pick disease, is a storage disorder with pulmonary involvement but few respiratory symptoms in adults. However, the disease may evolve towards clinically relevant respiratory symptoms with referral to the pulmonologist for management and care. Based on two case reports illustrating respiratory impairment, the aim of this work was to review clinical features, diagnosis, respiratory prognostic and therapeutics for the pulmonologist. Overall, storage disorder should be suspected in the presence of hepatosplenomegaly and interstitial lung disease. Concomitant thrombopenia or hyperlipidemia should also draw attention. Following recent consensus guidelines, diagnosis is based on enzyme assay for ASM activity in blood, with subsequent gene sequencing once the biochemical diagnosis has been confirmed. Disease is slowly progressive and the main causes of death are respiratory and liver failure. Presence of emphysema lesions or worsening of respiratory symptoms should call for the intensification of treatment. Though enzyme replacement therapy is a promising way of development, lung transplantation might be considered for these patients in the absence of contraindication.
gene therapies
2025-10-12 | Current and Emerging Treatments for Acid Sphingomyelinase Deficiency.
Acid sphingomyelinase deficiency is an ultra-rare disease characterised by generalised storage of sphingomyelin, caused by deficiency of the lysosomal enzyme acid sphingomyelinase, owing to the presence of biallelic pathogenic variants in the SMPD1 gene. The main disease manifestations are in the liver, spleen, lung and bone - with some patients having also involvement of the central nervous system. Patients show variable degrees of anaemia, thrombocytopenia and lipid abnormalities, among other findings. Clinically, acid sphingomyelinase deficiency spans from an acute neurovisceral form, with neurological involvement and early death (type A), to a chronic visceral disease, with no or minimal neurological manifestations (type B). An intermediate form, with chronic neurovisceral involvement, is presented by some patients (type A/B). Diagnosis involves the measurement of biomarkers, an assay of enzyme activity and genetic testing. Until a few years ago, treatment was mainly dependent on symptomatic management and bone marrow or solid organ (liver and/or lung) transplantation. In 2022, a specific enzyme replacement therapy with olipudase alfa was approved, and the results available indicate that it changed the therapeutic landscape for patients with acid sphingomyelinase deficiency type B and A/B. Research is being developed to address the needs of patients with acid sphingomyelinase deficiency type A, with gene therapy remaining as a promising approach.
2024-05-07 | Overview of clinical, molecular, and therapeutic features of Niemann–Pick disease (types A, B, and C): Focus on therapeutic approaches
Abstract Niemann–Pick disease (NPD) is another type of metabolic disorder that is classified as lysosomal storage diseases (LSDs). The main cause of the disease is mutation in the SMPD1 (type A and B) or NPC1 or NPC2 (type C) genes, which lead to the accumulation of lipid substrates in the lysosomes of the liver, brain, spleen, lung, and bone marrow cells. This is followed by multiple cell damage, dysfunction of lysosomes, and finally dysfunction of body organs. So far, about 346, 575, and 30 mutations have been reported in SMPD1 , NPC1 , and NPC2 genes, respectively. Depending on the type of mutation and the clinical symptoms of the disease, the treatment will be different. The general aim of the current study is to review the clinical and molecular characteristics of patients with NPD and study various treatment methods for this disease with a focus on gene therapy approaches.
2013-08-22 | Cholesterol trapping in Niemann-Pick disease type B fibroblasts can be relieved by expressing the phosphotyrosine binding domain of GULP.
Impairment of acid sphingomyelinase (SMase) results in accumulation of sphingomyelin (SM) and cholesterol in late endosomes, the hallmarks of a lysosomal storage disease. We describe cellular lipid metabolism in fibroblasts from two patients with novel compound heterozygote mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene manifesting as Niemann-Pick disease type B (NPB) and demonstrate mechanisms to overcome the storage defect. Using biochemical assays and confocal microscopy, we provide evidence that accumulated lysosomal SM and cholesterol can be released by different treatments. Defective SMase activity in these fibroblasts results in a 2.5-fold increased cellular mass of SM and cholesterol, increased de novo endogenous cholesterol synthesis, and decreased cholesterol esterification, demonstrating impaired intracellular cholesterol homeostasis. Depletion of exogenous addition of cholesterol for 24 hours or addition of the cholesterol acceptor apolipoprotein A-I are sufficient to restore normal homeostatic responses. In an effort to correct the lysosomal storage phenotype of NPB, we infected the fibroblasts with a lentivirus expressing the phosphotyrosine binding domain of the adapter protein GULP (PTB-GULP). We have previously shown that expression of PTB-GULP in Chinese hamster ovary cells promotes intracellular cholesterol trafficking and ABCA1-mediated cholesterol efflux. We find that expression of PTB-GULP in NPB fibroblasts results in increased ABCA1 expression, increased cellular cholesterol efflux and lysosomal cholesterol redistribution, independent of the impaired SMase and cholesterol presence. We provide extensive functional characterization of a novel compound heterozygote mutation and provide a novel functional mechanism to overcome lysosomal storage disease defects.
1992-04-15 | Retroviral-mediated transfer of the human acid sphingomyelinase cDNA: correction of the metabolic defect in cultured Niemann-Pick disease cells.
Types A and B Niemann-Pick disease (NPD) result from inherited deficiencies of the lysosomal hydrolase, acid sphingomyelinase (ASM; sphingomyelin cholinephosphohydrolase, EC 3.1.4.12). To evaluate the feasibility of somatic gene therapy for the treatment of these disorders, retroviral-mediated gene transfer was used to introduce the full-length ASM cDNA into cultured fibroblasts from two unrelated type A NPD patients. The ASM activities in these cells were less than 4% of mean normal levels, and, consequently, they accumulated approximately 3-fold elevated levels of sphingomyelin. After retroviral-mediated transfer of the ASM cDNA, ASM activities in the NPD cells increased to levels up to 16-fold those found in normal fibroblasts. In addition, the sphingomyelin content was reduced to normal levels, indicating that the vector-encoded enzyme was properly targeted to lysosomes, where it was enzymatically active and able to degrade the accumulated substrate. In situ cell-loading studies also were undertaken to evaluate the effects of retroviral-mediated gene transfer on the pathology of NPD fibroblasts. When a pyrene derivative of sphingomyelin was introduced into the lysosomes of cultured fibroblasts from a type A NPD patient by using apolipoprotein E-mediated endocytosis, only approximately 6% of the delivered substrate was degraded. In contrast, normal cells and NPD cells transduced (i.e., "corrected") by retroviral-mediated gene transfer could degrade approximately 80% of the delivered sphingomyelin. These results provided further evidence that retroviral-mediated gene transfer may be used to correct the pathology of NPD cells. Cell-loading studies were also used to develop a selection system for discriminating between NPD cells and those transduced by retroviral-mediated gene transfer. This selection scheme was based on the fluorescence emission of intact NPD cells, which, when loaded with pyrene-labeled sphingomyelin, was 3- to 5-fold that of normal or transduced cells. As a consequence, the NPD and transduced cells could be efficiently sorted by flow cytometry with a fluorescence-activated cell sorter. In addition, the NPD cells could be selectively killed by photosensitization after irradiation with a long-wavelength UV light. These results should permit direct selection of ASM-expressing cells after retroviral-mediated gene transfer without the need to preselect for a cotransferred marker gene.
small molecules
2026-07-03 | The Sphingolipid Balance and Endothelial Dysfunction in Lysosomal Storage Diseases: Shared Mechanisms in Gaucher, Niemann–Pick and Fabry Disease
Endothelial dysfunction underlies many cardiovascular and metabolic diseases. Lysosomal storage disorders, particularly sphingolipidoses, cause intracellular accumulation of specific sphingolipids due to inherited enzyme defects. This review focuses on Gaucher, Niemann–Pick (types A, B, A/B) and Fabry diseases, selected because they exhibit clinically significant cardiovascular manifestations and each accumulates a distinct sphingolipid—glucocerebroside, sphingomyelin, or globotriaosylceramide—allowing comparative analysis of how different metabolic defects converge on similar endothelial phenotypes. We summarize current knowledge on how substrate accumulation disrupts the ceramide/sphingosine-1-phosphate (S1P) rheostat, affecting NO synthase, vascular permeability, inflammation, angiogenesis, autophagy and cell death. Common and disease-specific changes in endothelial morphology and barrier function are discussed. Importantly, direct experimental evidence for endothelial involvement in Gaucher and Niemann–Pick diseases remains scarce; most mechanistic insights derive from non-endothelial cell models, highlighting a significant gap that underscores the need for targeted endothelial studies. Deficiencies of GBA1, SMPD1, and GLA each modulate S1P and ceramide production through distinct pathways, yet all three conditions share similar functional endothelial alterations driven by disrupted sphingolipid homeostasis. Understanding these common mechanisms opens new perspectives for diagnostic biomarkers and therapeutic strategies aimed at restoring sphingolipid balance in the endothelium, though further research is required to validate these findings in endothelial-specific contexts.
2026-04-26 | Curcumin controls lysosomal acidification and exocytosis to ameliorate lysosomal cholesterol accumulation in Niemann–Pick type C disease
Abstract Background and Purpose Niemann–Pick type C disease (NPCD) is a rare and fatal lysosomal storage disorder. There are limited therapies for NPCD, although multiple small‐molecule compounds have shown therapeutic potential for NPCD. Curcumin (CUR), a polyphenolic compound enriched in turmeric, has cholesterol‐lowering effects via regulating intestinal cholesterol absorption and liver cholesterol synthesis. CUR normalises sphingolipid trafficking and stimulates exosome/microvesicle release, increases cytosolic Ca 2+ levels, and enhances lysosomal activation via mTOR suppression and TFEB activation. How CUR specifically targets lysosomal cholesterol has not been fully clarified. Experimental Approach Effects of curcumin on lysosomal cholesterol accumulation were evaluated in NPC1 cell models. Filipin staining, immunofluorescence, surface LAMP1 and NAGase activity and Cathepsin B activity were investigated to evaluate lysosomal cholesterol, TFEB translocation, lysosomal exocytosis and hydrolytic activity. Lysosomal acidification was determined by Lysotracker Red, Oregon Green, and sfGFP/mCherry transfection. CRISPR/Cas9 and siRNA interference were used to investigate the role of TFEB/TFE3 and TRPML1 in curcumin‐induced cholesterol reduction. Key Results CUR alleviates lysosomal cholesterol accumulation in NPC1 cells in a TFEB‐ and TFE3‐dependent manner. CUR enhanced lysosomal acidity and promoted calcium‐dependent lysosomal exocytosis, which contributed to CUR‐mediated lysosomal cholesterol clearance. The combination of CUR with specific agonists (ML‐SAs) of MCOLN1/TRPML1, a lysosomal cation channel required for lysosomal exocytosis, improved lysosomal cholesterol clearance. Conclusion and Implications CUR reduces lysosomal cholesterol accumulation in NPC1 cells by activating TFEB/TFE3 pathways and promoting Ca 2+ ‐ and TRPML1‐dependent lysosomal exocytosis. These findings support curcumin and its analogues as potential therapeutics for NPCD and other diseases of lysosomal storage.
2026-04-10 | Zuclopenthixol inhibits residual activity of acid sphingomyelinase in Niemann pick disease type B: a case report with in vitro validation.
Niemann-Pick disease type B (NPD-B) is a rare lysosomal storage disorder characterized by residual activity of acid sphingomyelinase (ASM). While functional inhibitors of ASM (FIASMAs) are widely prescribed as psychotropic medications, they may pose a particular risk to patients with NPD-B by further reducing the already impaired enzymatic function. Here, we report the case of a 20-year-old male with genetically confirmed NPD-B who experienced rapid clinical deterioration following the administration of zuclopenthixol, a drug not previously associated with FIASMA activity. Within 48 hours of treatment initiation, the patient developed profound lethargy and markedly elevated creatine kinase (CK) levels of up to 22,000 U/L, consistent with rhabdomyolysis. Symptoms resolved quickly after discontinuation of zuclopenthixol. In vitro experiments using a radioactive [1 4 C]-sphingomyelin assay in Jurkat cells demonstrated that zuclopenthixol dose-dependently inhibited ASM activity by up to 71.5%. Zuclopenthixol had not previously been recognized as a FIASMA and might therefore have been considered a rational choice for treating patients with NPD-B. Our findings challenge this assumption by identifying zuclopenthixol as a potent inhibitor of ASM activity. This novel insight is of high clinical relevance, given the frequent use of antipsychotics in the management of neuropsychiatric symptoms in lysosomal storage disorders. We propose that zuclopenthixol and other potential FIASMAs be carefully re-evaluated for use in this vulnerable patient population.
2026-01-01 | Metabolic improvement in patients with acid sphingomyelinase deficiency following intravenous trehalose administration: an untargeted pharmacometabolomic study
Abstract Background Acid sphingomyelinase deficiency (ASMD) A and B, historically known as Niemann-Pick (NP) types A (NPA) and B (NPB), are life-threatening and rare inherited lysosomal storage disorders, caused by a deficiency in the acid sphingomyelinase enzyme activity. The negative outcome of this deficiency is the sphingomyelin (SM) accumulation in different organs and tissues. Trehalose is a natural disaccharide with neuroprotective and autophagy-inducing abilities that has recently been shown to improve clinical and biochemical features of patients with ASMD A/B. We previously showed that trehalose can reduce the serum levels of sphingomyelins and improve disease symptoms caused by lipid accumulation in ASMD A/B patients. Aim The aim of this study was to investigate the serum metabolome changes in five patients with ASMD A/B, who received 15 g/week of trehalose intravenously for three months, using an untargeted gas chromatography-mass spectrometry (GC-MS) method. Methods and materials GC-MS technique was used to assess the serum metabolic profile of patients with ASMD A/B. MSDIAL was used for data processing, and multivariate data analysis including Principal Component Analysis (PCA), and Orthogonal projections to latent structures discriminant analysis (OPLS-DA) algorithms were carried out using SIMCA. Results OPLS-DA model revealed significant changes in several serum metabolites including phosphate (P = 0.0019), sorbitol (P = 0.00009), myoinositol (P = 0.02), threonine (P = 0.01), lactic acid (P = 0.0001), 1-monopalmitin (P = 0.01), threitol (P = 0.002), ribitol (P = 0.008), and D-ribose (P = 0.007) following trehalose treatment. Conclusion The findings revealed that the beneficial effects of trehalose in patients with ASMD might be mediated by metabolic alterations. A clear shift in glucose metabolism in favor of less fatty acid production together with facilitating the breakdown of sphingomyelins is involved in the observed protective activity.
2025-02-07 | Short-Term Acid Sphingomyelinase Deficiency Exerts Proinflammatory and Antiapoptotic Effects during LPS-induced Lung Injury in Mice
Lysosomal acid sphingomyelinase (ASM; SMPD1) deficiency causes Niemann-Pick disease that, in type B, manifests with interstitial lung disease and susceptibility to infections. Constitutional Smpd1 (Smpd1-/- mouse) deletion causes lung inflammation with foamy dysfunctional macrophages but is protective against acute lung injury. It is unknown whether these manifestations are a result of progressive accumulation of sphingomyelin, decreased ceramide, or compensatory alterations in sphingolipid metabolism. We developed a conditional knockout mouse, CAGG-CreERTM × Smpd1fl/fl, induced by tamoxifen (5 wk), with decreased Smpd1 expression (by 75%) and ASM activity (by up to 40%). We investigated how brief postdevelopmental ASM insufficiency affects lung sphingolipids and pathology, including after LPS-induced injury. Compared with control animals, Smpd1fl/fl mice exhibited modest sphingomyelin elevation with lower palmitoyl/lignoceroyl ceramide (C16/C24) ratios and increased de novo sphingolipid synthesis and sphingosine-1-phosphate concentrations. At 3 days after LPS instillation (20 μg), control mice had increased lung (neutrophilic and monocytic) inflammation and apoptosis; Smpd1fl/fl mice showed more exuberant inflammation, but had significantly reduced apoptosis, particularly in endothelial cells. During repair phase (6-9 d), Smpd1fl/fl lungs had increased cell proliferation with reduced accumulation of autophagosome-tagging p62/SQSTM1. These results indicate that before developing lysosomal lipid storage, ASM insufficiency inhibits stress-induced lung apoptosis and promotes compensatory sphingolipid changes that favor exuberant inflammatory responses to LPS. Overall, ASM inhibition limits lung vascular injury and may stimulate repair after inflammatory insults. These results provide novel insights into the function of ASM in the lung, which are relevant to understanding the pathogenesis and complications of Niemann-Pick disease and the role of distinct sphingolipid metabolites in lung injury and repair.
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