RARE DISEASE
Infantile neurovisceral acid sphingomyelinase deficiency
Infantile neurovisceral acid sphingomyelinase deficiency
Infantile neurovisceral acid sphingomyelinase deficiency
Synonyms: Infantile neurovisceral ASMD, NPD-A, Niemann-Pick disease type A
Synonyms: Infantile neurovisceral ASMD, NPD-A, Niemann-Pick disease type A
Synonyms: Infantile neurovisceral ASMD, NPD-A, Niemann-Pick disease type A
Drug discovery
2
drugs
With orphan designations
Overview
Infantile neurovisceral acid sphingomyelinase deficiency (ASMD type A) is a fatal autosomal recessive lysosomal storage disorder caused by SMPD1 mutations, resulting in deficient sphingomyelin metabolism. It manifests in early infancy with rapid-onset hepatosplenomegaly, failure to thrive, and progressive neurodegeneration. Cherry-red maculae, respiratory insufficiency, and developmental regression occur by 6–12 months. Death typically occurs by age 3 due to respiratory or liver failure [1][3][5][12].
Burden
Morbidity: 100% experience hepatosplenomegaly, thrombocytopenia, and progressive lung/liver dysfunction; 92% develop developmental delay/regression [2][5][14].
Mortality: Median survival 2.4 years; 90% die by age 3 [2][5][12].
Caregiver impact: Requires intensive multidisciplinary care, home healthcare, and frequent hospitalization [2][9].
Therapies
Supportive care: Nutritional support (gastrostomy), respiratory interventions (supplemental oxygen), infection management, and spasticity control [9][12].
No disease-modifying therapies: Enzyme replacement therapy (olipudase alfa) approved for non-neurologic ASMD types; ineffective for neurodegeneration in type A [7][10][14].
Experimental approaches: Gene therapy and neural progenitor injections remain investigational [9].
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare respiratory diseases, rare transplant-related disorders
Research Papers
156 drug discovery papers about Infantile neurovisceral acid sphingomyelinase deficiency, with 2 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
156 drug discovery papers about Infantile neurovisceral acid sphingomyelinase deficiency, with 2 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
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.
2018-05-09 | Limited benefits of presymptomatic cord blood transplantation in neurovisceral acid sphingomyelinase deficiency (ASMD) intermediate type.
Acid sphingomyelinase (ASM) deficient Niemann-Pick disease is a lysosomal storage disorder resulting from mutations in the SMPD1 gene. The clinical spectrum distinguishes a severe infantile neurological form (type A), a non-neurological visceral form (type B) and a rare intermediate neurovisceral form. We report the first case of presymptomatic cord blood transplantation in a child with the intermediate type of ASM deficiency due to a homozygous Tyr369Cys mutation, whose affected elder brother had developed neurodevelopmental delay from 19 months of age, and had died from severe visceral complications at the age of 3. In the transplanted propositus, neurological deterioration became evident by 4 years of age; the child was alive at age 8, although severely disabled. Whereas the transplant prevented visceral progression and early death, it could only delay neurocognitive deterioration.
2007-06-01 | Injection of mouse and human neural stem cells into neonatal Niemann-Pick A model mice.
Cloned mouse C17.2 neural stem cells (NSCs) or human NSCs were injected into five CNS sites in very large numbers (100,000 cells/site, or a total of 500,000 cells) into 18 neonatal mice homozygous for a targeted deletion (knockout) of the acid sphingomyelinase (ASM) gene (called ASMKO mice), a faithful model of human Niemann-Pick type A (NP-A) disease, and into 10 wild-type mice, all on the C57BL/6J background. Injected mice were not immunosuppressed, and all survived to adulthood. Non-injected ASMKO controls had developed widespread neuronal and glial vacuolation and lysosomal accumulation of sphingomyelin and cholesterol when examined histologically at 16 weeks of age. Unlike children with NP-A disease, the ASMKO mice also lose cerebellar Purkinje neurons progressively, are ataxic, and show parallel progressive declines in rotorod performance. At 16 weeks NSC-injected mice showed a dramatic decrease in neuronal and glial vacuolation (by standard histological staining) and in cholesterol accumulation (by filipin fluorescence staining) throughout the cerebral neocortex, hippocampal formation, striatum and cerebellum, with lesser but clear improvement throughout the brainstem. Improvement was modestly but consistently better in human HFT13-injected than in mouse C17.2-injected ASMKO mice. Improvement in the ASMKO brains was more widespread than the distribution of NSCs, an indication that ASM must have been secreted and diffused at therapeutic concentrations beyond the territory occupied by NSCs. However, though Purkinje cell rescue has been achieved with NSCs in some other disease models, loss of Purkinje neurons and decline in rotorod performance were still present in injected ASMKO mice.
2004-11-24 | Intracerebral Transplantation of Adult Mouse Neural Progenitor Cells into the Niemann-Pick-A Mouse Leads to a Marked Decrease in Lysosomal Storage Pathology
Niemann-Pick disease is caused by a genetic deficiency in acid sphingomyelinase (ASM) leading to the intracellular accumulation of sphingomyelin and cholesterol in lysosomes. In the present study, we evaluated the effects of direct intracerebral transplantation of neural progenitor cells (NPCs) on the brain storage pathology in the ASM knock-out (ASMKO) mouse model of Type A Niemann-Pick disease. NPCs derived from adult mouse brain were genetically modified to express human ASM (hASM) and were transplanted into multiple regions of the ASMKO mouse brain. Transplanted NPCs survived, migrated, and showed region-specific differentiation in the host brain up to 10 weeks after transplantation (the longest time point examined). In vitro , gene-modified NPCs expressed up to 10 times more and released five times more ASM activity into the culture media compared with nontransduced NPCs. In vivo , transplanted cells expressed hASM at levels that were barely detectable by immunostaining but were sufficient for uptake and cross-correction of host cells, leading to reversal of distended lysosomal pathology and regional clearance of sphingomyelin and cholesterol storage. Within the host brain, the area of correction closely overlapped with the distribution of the hASM-modified NPCs. No correction of pathology occurred in brain regions that received transplants of nontransduced NPCs. These results indicate that the presence of transduced NPCs releasing low levels of hASM within the ASMKO mouse brain is necessary and sufficient to reverse lysosomal storage pathology. Potentially, NPCs may serve as a useful gene transfer vehicle for the treatment of CNS pathology in other lysosomal storage diseases and neurodegenerative disorders.
2002-05-01 | Intracerebral transplantation of mesenchymal stem cells into acid sphingomyelinase–deficient mice delays the onset of neurological abnormalities and extends their life span
Types A and B Niemann-Pick disease (NPD) are lysosomal storage disorders resulting from loss of acid sphingomyelinase (ASM) activity. We have used a knockout mouse model of NPD (ASMKO mice) to evaluate the effects of direct intracerebral transplantation of bone marrow–derived mesenchymal stem cells (MSCs) on the progression of neurological disease in this disorder. MSCs were transduced with a retroviral vector to overexpress ASM and were injected into the hippocampus and cerebellum of 3-week-old ASMKO pups. Transplanted cells migrated away from the injection sites and survived at least 6 months after transplantation. Seven of 8 treated mice, but none of the untreated controls, survived for ≥ 7 months after transplant. Survival times were greater in sex-matched than in sex-mismatched transplants. Transplantation significantly delayed the Purkinje cell loss that is characteristic of NPD, although the protective effect declined with distance from the injection site. Overall ASM activity in brain homogenates was low, but surviving Purkinje cells contained the retrovirally expressed human enzyme, and transplanted animals showed a reduction in cerebral sphingomyelin. These results reveal the potential of treating neurodegenerative lysosomal storage disorders by intracerebral transplantation of bone marrow–derived MSCs.
small molecules
2026-08-13 | Targeting CD44 reverses sphingomyelin-induced oligodendrocyte maturation arrest in acid sphingomyelinase deficiency.
Loss-of-function mutations in the smpd1 gene cause acid sphingomyelinase deficiency (ASMD). Early neurodegeneration and lethality characterize its infantile neurovisceral form (type A). While neuronal dysfunction was traditionally considered the primary driver of the pathology, recent evidence suggests that dysmyelination and microgliosis are not merely secondary features. Specifically, myelin debris undermines the protective role of microglia, contributing to neuroinflammation and neuronal death. Herein, we examined central myelin and oligodendrocyte lineage progression in ASM knockout mice. We show that early-onset dysmyelination results from compromised oligodendrocyte maturation driven by aberrant sphingomyelin-mediated signaling. Transcriptomic profiling revealed that mature oligodendrocytes in these mice retain a gene expression signature similar to oligodendrocyte precursor cells, indicating a differentiation arrest. The cell adhesion molecule CD44 remained significantly upregulated in mature ASMko oligodendrocytes. Pharmacological inhibition of CD44 with verbascoside rescued oligodendroglial maturation in primary culture. Verbascoside administration in vivo restored myelin integrity and improved motor behavior. These findings establish that sphingomyelin homeostasis is critical for oligodendrocyte maturation and identify myelin defects as both primary pathological triggers and therapeutic targets for ASMD with neurologic symptoms.
2026-03-09 | A Colletotrichum orbiculare-based fungal model recapitulates conserved cellular defects of Niemann–Pick type C disease and enables therapeutic evaluation
Niemann–Pick type C (NPC) disease is a fatal lysosomal storage disorder caused by mutations in NPC1 or NPC2, leading to lipid accumulation and progressive neurodegeneration. Current mammalian models recapitulate major pathological features but are limited by long disease courses and low throughput. Here, we establish the plant-pathogenic fungus Colletotrichum orbiculare as a scalable and phenotypically robust eukaryotic model of NPC. Introduction of disease-associated point mutations into CoNpc1 or CoNpc2 abolished pathogenicity, demonstrating that NPC dysfunction compromises lipid-dependent morphogenesis essential for host penetration. Expression of human NPC1 complemented the fungal deletion mutant, highlighting conserved sterol transport functions across kingdoms. Pharmacological treatments with miglustat and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) restored pathogenicity through distinct lipid pathways: miglustat normalized sphingolipid metabolism, whereas HP-β-CD alleviated sterol mislocalization. These complementary rescue routes reveal that perturbations in NPC homologs converge on lipid-dependent morphogenesis closely linked to actin organization. By linking lipid metabolism, actin cytoskeletal organization, and pharmacological rescue to a measurable infection outcome, this fungal model provides a tractable and biologically faithful platform for mechanistic and therapeutic exploration in NPC disease.
2026-01-08 | Metabolic improvement in patients with acid sphingomyelinase deficiency following intravenous trehalose administration: an untargeted pharmacometabolomic study.
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.
2026-01-01 | Modulating Protein Folding in Niemann-Pick Type C Disease
Lysosomal storage diseases (LSDs) are a class of more than 60 inherited disorders characterized by the accumulation of lysosomal substrates and organellar dysfunction. While clinical manifestations of LSDs are heterogenous, over two-thirds of LSDs affect the central nervous system. One such disorder is Niemann-Pick type C (NPC) disease, a rare, autosomal recessive LSD that causes severe, progressive neurodegeneration and early death. NPC disease is primarily caused by mutations in the NPC1 gene (95% of cases), which encodes for the NPC1 protein. NPC1 is a large, transmembrane glycoprotein required for the export of cholesterol from late endosomes and lysosomes. Consequently, mutations in NPC1 lead to abnormal cholesterol and secondary lipid storage within these compartments. This disruption of intracellular lipid trafficking impairs diverse cellular functions, resulting in autophagy disruption, calcium homeostasis dysregulation, lysosomal membrane permeabilization, mitochondrial abnormalities, and cell death pathway activation. Recently, two therapeutics received FDA approval for treatment of NPC disease. While this is a significant step forward for patients, these compounds are limited in their efficacy and clinical need remains significant. This dissertation aims to address this by targeting mutant NPC1 protein folding as a strategy to treat NPC disease. In Chapter 2, this thesis presents work retesting previously published protein folding compounds using recently developed human stem cell-derived induced neurons and a new humanized NPC disease mouse. This work identifies one compound, mo56-hydroxycholesterol (mo56hc), effective in both models, that acts directly on mutant NPC1. In Chapter 3, this thesis presents work showing that structural derivatization of mo56hc enables a new compound, NDNPC-2, to be more effective and stable. Further, this work assesses in vivo target engagement by NDNPC-2. Finally, Chapter 4 summarizes these findings, discusses outstanding questions, and presents future directions. This work seeks to understand and improve NPC disease pathogenesis by targeting mutant NPC1 folding. Taken together, this work will contribute knowledge and tools to further the development of more effective Niemann-Pick type C disease therapeutics.
2025-11-01 | Computational Analysis of SMPD1 Mutants and Their Binding Affinity with Desipramine: A Therapeutic Insight into Niemann–Pick Disease Type A
Abstract Niemann–Pick disease type A (NPD‐A) is a severe metabolic disorder caused by the deficiency of acid sphingomyelinase (ASM) due to mutations in the SMPD1 gene. The objective of this study was to identify and characterize the most deleterious SMPD1 mutations using a computational pipeline. A total of 177 mutations retrieved from public databases were evaluated based on pathogenicity, protein stability, biophysical properties, conservation analysis, and phenotypic relevance. Among these, two mutations, D253H and Y539H emerged as the most potentially pathogenic, causing significant disruption in protein function and stability. To further understand the structural implications, molecular docking was performed using desipramine as the ligand. The docking scores were − 4.63 kcal/mol for the native structure and − 6.16 kcal/mol and − 6.30 kcal/mol for D253H and Y539H, respectively, indicating for the mutants. Molecular dynamics (MD) simulations were then carried out, revealing improved structural stability, compactness, hydrogen bonding (H‐bond), and flexibility in the mutant complexes. Principal component analysis (PCA) and MM‐PBSA calculations demonstrated reduced conformational fluctuations and stronger binding energies in all desipramine‐bound complexes. These findings contribute valuable insights into the pathogenic mechanisms of SMPD1 mutations in NPD‐A offer potential leads for future therapeutic interventions targeting ASM dysfunction.
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.
2025-01-01 | Exploring the boundaries of Niemann-Pick disease type A/B: a report of a case and review of literature
Abstract Background Acid sphingomyelinase deficiency (ASMD), also known as Niemann-Pick disease types A and B, is a rare autosomal recessive lysosomal storage disorder caused by SMPD1 mutations. It is characterized by sphingomyelin accumulation and a broad clinical spectrum ranging from severe neurodegeneration in type A to a milder visceral phenotype in type B. Intermediate forms (type A/B) show overlapping features of both subtypes. Case presentation We report a 6-month-old boy with ASMD type A/B who first presented with meningoencephalitis and a single seizure most likely secondary to an intercurrent viral infection rather than a primary disease manifestation. Subsequent evaluation revealed multiple systemic red-flag features including marked hepatosplenomegaly, severe growth failure, a cherry-red spot, macroglossia, dysmorphic facial features, recurrent pneumonia, and bilateral sensorineural hearing loss. Laboratory investigations demonstrated elevated liver enzymes and cerebrospinal fluid abnormalities, while auditory brainstem response confirmed the hearing impairment. Enzyme assay confirmed reduced ASM activity, and targeted SMPD1 genetic sequencing identified a homozygous frameshift mutation classified as pathogenic according to ACMG criteria, establishing the diagnosis of an intermediate ASMD phenotype. Conclusion This case highlights the diagnostic challenges posed by ASMD type A/B, particularly when the initial presentation mimics an acute infection. The overlap of coincidental infectious illness with systemic red-flag features, the clinical variability of intermediate phenotypes, and the rarity of the disorder all contribute to delayed recognition. These factors underscore the importance of maintaining a high index of suspicion and pursuing early metabolic and genetic testing in atypical pediatric presentations. Trial registration Not applicable.
2024-12-19 | Endothelial and neuronal engagement by AAV-BR1 gene therapy alleviates neurological symptoms and lipid deposition in a mouse model of Niemann-Pick type C2
Background: Patients with the genetic disorder Niemann-Pick type C2 disease (NP-C2) suffer from lysosomal accumulation of cholesterol causing both systemic and severe neurological symptoms. In a murine NP-C2 model, otherwise successful intravenous Niemann-Pick C2 protein (NPC2) replacement therapy fails to alleviate progressive neurodegeneration as infused NPC2 cannot cross the blood-brain barrier (BBB). Genetic modification of brain endothelial cells (BECs) is thought to enable secretion of recombinant proteins thereby overcoming the restrictions of the BBB. We hypothesized that an adeno-associated virus (AAV-BR1) encoding the Npc2gene could cure neurological symptoms in Npc2-/- mice through transduction of BECs, and possibly neurons via viral passage across the BBB. Methods: Six weeks old Npc2-/- mice were intravenously injected with the AAV-BR1-NPC2 vector. Composite phenotype scores and behavioral tests were assessed for the following six weeks and visually documented. Post-mortem analyses included gene expression analyses, verification of neurodegeneration in Purkinje cells, determination of NPC2 transduction in the CNS, assessment of neuroinflammation, quantification of gangliosides and co-detection of cholesterol with NPC2 in degenerating neurons. Results: Treatment with the AAV-BR1-NPC2 vector improved motor functions, reduced neocortical inflammation, and preserved Purkinje cells in most of the mice, referred to as high-responders. The vector exerted tropism for BECs and neurons resulting in a widespread NPC2 distribution in the brain with a concomitant reduction of cholesterol in adjacent neurons, presumably not transduced by the vector. Mass spectrometry imaging revealed distinct lipid alterations in the brains of Npc2-/- mice, with increased GM2 and GM3 ganglioside accumulation in the cerebellum and hippocampus. AAV-BR1-NPC2 treatment partially normalized these ganglioside distributions in high responders, including restoration of lipid profiles towards those of Npc2+/+ controls. Conclusion: The data suggests cross-correcting gene therapy to the brain via delivery of NPC2 from BECs and neurons.
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.
2022-05-12 | A novel strategy for deliveringNiemann‐Pick typeC2proteins across the blood–brain barrier using the brain endothelial‐specificAAV‐BR1virus
Abstract Treating central nervous system (CNS) diseases is complicated by the incapability of numerous therapeutics to cross the blood–brain barrier (BBB), mainly composed of brain endothelial cells (BECs). Genetically modifying BECs into protein factories that supply the CNS with recombinant proteins is a promising approach to overcome this hindrance, especially in genetic diseases, like Niemann Pick disease type C2 (NPC2), where both CNS and peripheral cells are affected. Here, we investigated the potential of the BEC‐specific adeno‐associated viral vector (AAV‐BR1) encoding NPC2 for expression and secretion from primary BECs cultured in an in vitro BBB model with mixed glial cells, and in healthy BALB/c mice. Transduced primary BECs had significantly increased NPC2 gene expression and secreted NPC2 after viral transduction, which significantly reversed cholesterol deposition in NPC2 deficient fibroblasts. Mice receiving an intravenous injection with AAV‐BR1‐NCP2‐eGFP were sacrificed 8 weeks later and examined for its biodistribution and transgene expression of eGFP and NPC2. AAV‐BR1‐NPC2‐eGFP was distributed mainly to the brain and lightly to the heart and lung, but did not label other organs including the liver. eGFP expression was primarily found in BECs throughout the brain but occasionally also in neurons suggesting transport of the vector across the BBB, a phenomenon also confirmed in vitro . NPC2 gene expression was up‐regulated in the brain, and recombinant NPC2 protein expression was observed in both transduced brain capillaries and neurons. Our findings show that AAV‐BR1 transduction of BECs is possible and that it may denote a promising strategy for future treatment of NPC2. image
proteins
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.
2025-10-03 | Lysosomal Storage Disorders
Abstract Lysosomes are intracellular organelles that are responsible for degrading and recycling macromolecules. Lysosomal diseases (LDs) are a group of rare inherited diseases caused by deleterious variants affecting genes that encode the lysosomal enzymes, their transporter or their cofactor. Among LDs that are associated with lung involvement and/or interstitial lung disease (ILD) acid sphingomyelinase deficiency [ASMD formerly called Niemann–Pick A, AB, and B diseases]) is the most common. An history of lower respiratory tract infections and exertional dyspnea are the most frequent respiratory manifestations. In ASMD, ILD is frequent and is usually associated with spleen and/or liver enlargement, low platelet count, and low level of high-density lipoprotein cholesterol. A restrictive lung functional pattern and a reduction in DLCO value are usually observed. Analysis of bronchoalveolar lavage fluid and lung biopsy showing foamy cells can orientate the diagnosis, based on the demonstration of an enzymatic deficiency in sphingomyelinase in the blood, associated with biallelic pathogenic variants of the SMPD1 gene. An enzyme replacement therapy (ERT), based on intravenous recombinant enzyme infusions (olipudase alfa), is available from 2021 with very encouraging results both in pediatric and adult patients affected with type B or AB. Olipudase alfa administration decreased liver and spleen volume, increased DLCO value and improved radiological lung involvement. Available enzyme replacement therapy supports an early diagnosis to implement therapy before any irreversible organ damage.
2021-09-24 | Apolipoprotein D-mediated preservation of lysosomal function promotes cell survival and delays motor impairment in Niemann-Pick type A disease.
Lysosomal Storage Diseases (LSD) are genetic diseases causing systemic and nervous system dysfunction. The glia-derived lipid binding protein Apolipoprotein D (ApoD) is required for lysosomal functional integrity in glial and neuronal cells, ensuring cell survival upon oxidative stress or injury. Here we test whether ApoD counteracts the pathogenic consequences of a LSD, Niemann Pick-type-A disease (NPA), where mutations in the acid sphingomyelinase gene result in sphingomyelin accumulation, lysosomal permeabilization and early-onset neurodegeneration. We performed a multivariable analysis of behavioral, cellular and molecular outputs in 12 and 24 week-old male and female NPA model mice, combined with ApoD loss-of-function mutation. Lack of ApoD in NPA mice accelerates cerebellar-dependent motor deficits, enhancing loss of Purkinje neurons. We studied ApoD expression in brain sections from a NPA patient and age-matched control, and the functional consequences of ApoD supplementation in primary human fibroblasts from two independent NPA patients and two control subjects. Cell viability, lipid peroxidation, and lysosomal functional integrity (pH, Cathepsin B activity, Galectin-3 exclusion) were examined. ApoD is endogenously overexpressed in NPA patients and NPA mouse brains and targeted to lysosomes of NPA patient cells, including Purkinje neurons and cultured fibroblasts. The accelerated lysosomal targeting of ApoD by oxidative stress is hindered in NPA fibroblasts, contributing to NPA lysosomes vulnerability. Exogenously added ApoD reduces NPA-prompted lysosomal permeabilization and alkalinization, reverts lipid peroxides accumulation, and significantly increases NPA cell survival. ApoD administered simultaneously to sphingomyelin overload results in complete rescue of cell survival. Our results reveal that ApoD protection of lysosomal integrity counteracts NPA pathology. ApoD supplementation could significantly delay not only the progression of NPA disease, but also of other LSDs through its beneficial effects in lysosomal functional maintenance.
2018-01-16 | Excess sphingomyelin disturbs ATG9A trafficking and autophagosome closure.
Sphingomyelin is an essential cellular lipid that traffics between plasma membrane and intracellular organelles until directed to lysosomes for SMPD1 (sphingomyelin phosphodiesterase 1)-mediated degradation. Inactivating mutations in the SMPD1 gene result in Niemann-Pick diseases type A and B characterized by sphingomyelin accumulation and severely disturbed tissue homeostasis. Here, we report that sphingomyelin overload disturbs the maturation and closure of autophagic membranes. Niemann-Pick type A patient fibroblasts and SMPD1-depleted cancer cells accumulate elongated and unclosed autophagic membranes as well as abnormally swollen autophagosomes in the absence of normal autophagosomes and autolysosomes. The immature autophagic membranes are rich in WIPI2, ATG16L1 and MAP1LC3B but display reduced association with ATG9A. Contrary to its normal trafficking between plasma membrane, intracellular organelles and autophagic membranes, ATG9A concentrates in transferrin receptor-positive juxtanuclear recycling endosomes in SMPD1-deficient cells. Supporting a causative role for ATG9A mistrafficking in the autophagy defect observed in SMPD1-deficient cells, ectopic ATG9A effectively reverts this phenotype. Exogenous C12-sphingomyelin induces a similar juxtanuclear accumulation of ATG9A and subsequent defect in the maturation of autophagic membranes in healthy cells while the main sphingomyelin metabolite, ceramide, fails to revert the autophagy defective phenotype in SMPD1-deficient cells. Juxtanuclear accumulation of ATG9A and defective autophagy are also evident in tissues of smpd1-deficient mice with a subsequent inability to cope with kidney ischemia-reperfusion stress. These data reveal sphingomyelin as an important regulator of ATG9A trafficking and maturation of early autophagic membranes.
other
2023-04-10 | Sphingomyelin 16:0 is a therapeutic target for neuronal death in acid sphingomyelinase deficiency.
Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder caused by mutations in the SMPD1 gene encoding for the acid sphingomyelinase (ASM). While intravenous infusion of recombinant ASM is an effective treatment for the peripheral disease, the neurological complications of ASMD remain unaddressed. It has been shown that aberrantly high level of total brain sphingomyelin (SM) is a key pathological event leading to neurodegeneration. Using mice lacking ASM (ASMko), which mimic the disease, we here demonstrate that among the SM species, SM16:0 shows the highest accumulation and toxicity in ASMko neurons. By targeting lysosomes, SM16:0 causes permeabilization and exocytosis of these organelles and induces oxidative stress and cell death. We also show that genetic silencing of Ceramide Synthase 5, which is involved in SM16:0 synthesis and overexpressed in the ASMko brain, prevents disease phenotypes in ASMko cultured neurons and mice. The levels of SM16:0 in plasma also show a strong correlation with those in brain that is higher than in liver, even at early stages of the disease. These results identify SM16:0 both as a novel therapeutic target and potential biomarker of brain pathology in ASMD.
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.
2018-05-09 | Limited benefits of presymptomatic cord blood transplantation in neurovisceral acid sphingomyelinase deficiency (ASMD) intermediate type.
Acid sphingomyelinase (ASM) deficient Niemann-Pick disease is a lysosomal storage disorder resulting from mutations in the SMPD1 gene. The clinical spectrum distinguishes a severe infantile neurological form (type A), a non-neurological visceral form (type B) and a rare intermediate neurovisceral form. We report the first case of presymptomatic cord blood transplantation in a child with the intermediate type of ASM deficiency due to a homozygous Tyr369Cys mutation, whose affected elder brother had developed neurodevelopmental delay from 19 months of age, and had died from severe visceral complications at the age of 3. In the transplanted propositus, neurological deterioration became evident by 4 years of age; the child was alive at age 8, although severely disabled. Whereas the transplant prevented visceral progression and early death, it could only delay neurocognitive deterioration.
2007-06-01 | Injection of mouse and human neural stem cells into neonatal Niemann-Pick A model mice.
Cloned mouse C17.2 neural stem cells (NSCs) or human NSCs were injected into five CNS sites in very large numbers (100,000 cells/site, or a total of 500,000 cells) into 18 neonatal mice homozygous for a targeted deletion (knockout) of the acid sphingomyelinase (ASM) gene (called ASMKO mice), a faithful model of human Niemann-Pick type A (NP-A) disease, and into 10 wild-type mice, all on the C57BL/6J background. Injected mice were not immunosuppressed, and all survived to adulthood. Non-injected ASMKO controls had developed widespread neuronal and glial vacuolation and lysosomal accumulation of sphingomyelin and cholesterol when examined histologically at 16 weeks of age. Unlike children with NP-A disease, the ASMKO mice also lose cerebellar Purkinje neurons progressively, are ataxic, and show parallel progressive declines in rotorod performance. At 16 weeks NSC-injected mice showed a dramatic decrease in neuronal and glial vacuolation (by standard histological staining) and in cholesterol accumulation (by filipin fluorescence staining) throughout the cerebral neocortex, hippocampal formation, striatum and cerebellum, with lesser but clear improvement throughout the brainstem. Improvement was modestly but consistently better in human HFT13-injected than in mouse C17.2-injected ASMKO mice. Improvement in the ASMKO brains was more widespread than the distribution of NSCs, an indication that ASM must have been secreted and diffused at therapeutic concentrations beyond the territory occupied by NSCs. However, though Purkinje cell rescue has been achieved with NSCs in some other disease models, loss of Purkinje neurons and decline in rotorod performance were still present in injected ASMKO mice.
2004-11-24 | Intracerebral Transplantation of Adult Mouse Neural Progenitor Cells into the Niemann-Pick-A Mouse Leads to a Marked Decrease in Lysosomal Storage Pathology
Niemann-Pick disease is caused by a genetic deficiency in acid sphingomyelinase (ASM) leading to the intracellular accumulation of sphingomyelin and cholesterol in lysosomes. In the present study, we evaluated the effects of direct intracerebral transplantation of neural progenitor cells (NPCs) on the brain storage pathology in the ASM knock-out (ASMKO) mouse model of Type A Niemann-Pick disease. NPCs derived from adult mouse brain were genetically modified to express human ASM (hASM) and were transplanted into multiple regions of the ASMKO mouse brain. Transplanted NPCs survived, migrated, and showed region-specific differentiation in the host brain up to 10 weeks after transplantation (the longest time point examined). In vitro , gene-modified NPCs expressed up to 10 times more and released five times more ASM activity into the culture media compared with nontransduced NPCs. In vivo , transplanted cells expressed hASM at levels that were barely detectable by immunostaining but were sufficient for uptake and cross-correction of host cells, leading to reversal of distended lysosomal pathology and regional clearance of sphingomyelin and cholesterol storage. Within the host brain, the area of correction closely overlapped with the distribution of the hASM-modified NPCs. No correction of pathology occurred in brain regions that received transplants of nontransduced NPCs. These results indicate that the presence of transduced NPCs releasing low levels of hASM within the ASMKO mouse brain is necessary and sufficient to reverse lysosomal storage pathology. Potentially, NPCs may serve as a useful gene transfer vehicle for the treatment of CNS pathology in other lysosomal storage diseases and neurodegenerative disorders.
2002-05-01 | Intracerebral transplantation of mesenchymal stem cells into acid sphingomyelinase–deficient mice delays the onset of neurological abnormalities and extends their life span
Types A and B Niemann-Pick disease (NPD) are lysosomal storage disorders resulting from loss of acid sphingomyelinase (ASM) activity. We have used a knockout mouse model of NPD (ASMKO mice) to evaluate the effects of direct intracerebral transplantation of bone marrow–derived mesenchymal stem cells (MSCs) on the progression of neurological disease in this disorder. MSCs were transduced with a retroviral vector to overexpress ASM and were injected into the hippocampus and cerebellum of 3-week-old ASMKO pups. Transplanted cells migrated away from the injection sites and survived at least 6 months after transplantation. Seven of 8 treated mice, but none of the untreated controls, survived for ≥ 7 months after transplant. Survival times were greater in sex-matched than in sex-mismatched transplants. Transplantation significantly delayed the Purkinje cell loss that is characteristic of NPD, although the protective effect declined with distance from the injection site. Overall ASM activity in brain homogenates was low, but surviving Purkinje cells contained the retrovirally expressed human enzyme, and transplanted animals showed a reduction in cerebral sphingomyelin. These results reveal the potential of treating neurodegenerative lysosomal storage disorders by intracerebral transplantation of bone marrow–derived MSCs.
small molecules
2026-08-13 | Targeting CD44 reverses sphingomyelin-induced oligodendrocyte maturation arrest in acid sphingomyelinase deficiency.
Loss-of-function mutations in the smpd1 gene cause acid sphingomyelinase deficiency (ASMD). Early neurodegeneration and lethality characterize its infantile neurovisceral form (type A). While neuronal dysfunction was traditionally considered the primary driver of the pathology, recent evidence suggests that dysmyelination and microgliosis are not merely secondary features. Specifically, myelin debris undermines the protective role of microglia, contributing to neuroinflammation and neuronal death. Herein, we examined central myelin and oligodendrocyte lineage progression in ASM knockout mice. We show that early-onset dysmyelination results from compromised oligodendrocyte maturation driven by aberrant sphingomyelin-mediated signaling. Transcriptomic profiling revealed that mature oligodendrocytes in these mice retain a gene expression signature similar to oligodendrocyte precursor cells, indicating a differentiation arrest. The cell adhesion molecule CD44 remained significantly upregulated in mature ASMko oligodendrocytes. Pharmacological inhibition of CD44 with verbascoside rescued oligodendroglial maturation in primary culture. Verbascoside administration in vivo restored myelin integrity and improved motor behavior. These findings establish that sphingomyelin homeostasis is critical for oligodendrocyte maturation and identify myelin defects as both primary pathological triggers and therapeutic targets for ASMD with neurologic symptoms.
2026-03-09 | A Colletotrichum orbiculare-based fungal model recapitulates conserved cellular defects of Niemann–Pick type C disease and enables therapeutic evaluation
Niemann–Pick type C (NPC) disease is a fatal lysosomal storage disorder caused by mutations in NPC1 or NPC2, leading to lipid accumulation and progressive neurodegeneration. Current mammalian models recapitulate major pathological features but are limited by long disease courses and low throughput. Here, we establish the plant-pathogenic fungus Colletotrichum orbiculare as a scalable and phenotypically robust eukaryotic model of NPC. Introduction of disease-associated point mutations into CoNpc1 or CoNpc2 abolished pathogenicity, demonstrating that NPC dysfunction compromises lipid-dependent morphogenesis essential for host penetration. Expression of human NPC1 complemented the fungal deletion mutant, highlighting conserved sterol transport functions across kingdoms. Pharmacological treatments with miglustat and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) restored pathogenicity through distinct lipid pathways: miglustat normalized sphingolipid metabolism, whereas HP-β-CD alleviated sterol mislocalization. These complementary rescue routes reveal that perturbations in NPC homologs converge on lipid-dependent morphogenesis closely linked to actin organization. By linking lipid metabolism, actin cytoskeletal organization, and pharmacological rescue to a measurable infection outcome, this fungal model provides a tractable and biologically faithful platform for mechanistic and therapeutic exploration in NPC disease.
2026-01-08 | Metabolic improvement in patients with acid sphingomyelinase deficiency following intravenous trehalose administration: an untargeted pharmacometabolomic study.
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.
2026-01-01 | Modulating Protein Folding in Niemann-Pick Type C Disease
Lysosomal storage diseases (LSDs) are a class of more than 60 inherited disorders characterized by the accumulation of lysosomal substrates and organellar dysfunction. While clinical manifestations of LSDs are heterogenous, over two-thirds of LSDs affect the central nervous system. One such disorder is Niemann-Pick type C (NPC) disease, a rare, autosomal recessive LSD that causes severe, progressive neurodegeneration and early death. NPC disease is primarily caused by mutations in the NPC1 gene (95% of cases), which encodes for the NPC1 protein. NPC1 is a large, transmembrane glycoprotein required for the export of cholesterol from late endosomes and lysosomes. Consequently, mutations in NPC1 lead to abnormal cholesterol and secondary lipid storage within these compartments. This disruption of intracellular lipid trafficking impairs diverse cellular functions, resulting in autophagy disruption, calcium homeostasis dysregulation, lysosomal membrane permeabilization, mitochondrial abnormalities, and cell death pathway activation. Recently, two therapeutics received FDA approval for treatment of NPC disease. While this is a significant step forward for patients, these compounds are limited in their efficacy and clinical need remains significant. This dissertation aims to address this by targeting mutant NPC1 protein folding as a strategy to treat NPC disease. In Chapter 2, this thesis presents work retesting previously published protein folding compounds using recently developed human stem cell-derived induced neurons and a new humanized NPC disease mouse. This work identifies one compound, mo56-hydroxycholesterol (mo56hc), effective in both models, that acts directly on mutant NPC1. In Chapter 3, this thesis presents work showing that structural derivatization of mo56hc enables a new compound, NDNPC-2, to be more effective and stable. Further, this work assesses in vivo target engagement by NDNPC-2. Finally, Chapter 4 summarizes these findings, discusses outstanding questions, and presents future directions. This work seeks to understand and improve NPC disease pathogenesis by targeting mutant NPC1 folding. Taken together, this work will contribute knowledge and tools to further the development of more effective Niemann-Pick type C disease therapeutics.
2025-11-01 | Computational Analysis of SMPD1 Mutants and Their Binding Affinity with Desipramine: A Therapeutic Insight into Niemann–Pick Disease Type A
Abstract Niemann–Pick disease type A (NPD‐A) is a severe metabolic disorder caused by the deficiency of acid sphingomyelinase (ASM) due to mutations in the SMPD1 gene. The objective of this study was to identify and characterize the most deleterious SMPD1 mutations using a computational pipeline. A total of 177 mutations retrieved from public databases were evaluated based on pathogenicity, protein stability, biophysical properties, conservation analysis, and phenotypic relevance. Among these, two mutations, D253H and Y539H emerged as the most potentially pathogenic, causing significant disruption in protein function and stability. To further understand the structural implications, molecular docking was performed using desipramine as the ligand. The docking scores were − 4.63 kcal/mol for the native structure and − 6.16 kcal/mol and − 6.30 kcal/mol for D253H and Y539H, respectively, indicating for the mutants. Molecular dynamics (MD) simulations were then carried out, revealing improved structural stability, compactness, hydrogen bonding (H‐bond), and flexibility in the mutant complexes. Principal component analysis (PCA) and MM‐PBSA calculations demonstrated reduced conformational fluctuations and stronger binding energies in all desipramine‐bound complexes. These findings contribute valuable insights into the pathogenic mechanisms of SMPD1 mutations in NPD‐A offer potential leads for future therapeutic interventions targeting ASM dysfunction.
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.
2025-01-01 | Exploring the boundaries of Niemann-Pick disease type A/B: a report of a case and review of literature
Abstract Background Acid sphingomyelinase deficiency (ASMD), also known as Niemann-Pick disease types A and B, is a rare autosomal recessive lysosomal storage disorder caused by SMPD1 mutations. It is characterized by sphingomyelin accumulation and a broad clinical spectrum ranging from severe neurodegeneration in type A to a milder visceral phenotype in type B. Intermediate forms (type A/B) show overlapping features of both subtypes. Case presentation We report a 6-month-old boy with ASMD type A/B who first presented with meningoencephalitis and a single seizure most likely secondary to an intercurrent viral infection rather than a primary disease manifestation. Subsequent evaluation revealed multiple systemic red-flag features including marked hepatosplenomegaly, severe growth failure, a cherry-red spot, macroglossia, dysmorphic facial features, recurrent pneumonia, and bilateral sensorineural hearing loss. Laboratory investigations demonstrated elevated liver enzymes and cerebrospinal fluid abnormalities, while auditory brainstem response confirmed the hearing impairment. Enzyme assay confirmed reduced ASM activity, and targeted SMPD1 genetic sequencing identified a homozygous frameshift mutation classified as pathogenic according to ACMG criteria, establishing the diagnosis of an intermediate ASMD phenotype. Conclusion This case highlights the diagnostic challenges posed by ASMD type A/B, particularly when the initial presentation mimics an acute infection. The overlap of coincidental infectious illness with systemic red-flag features, the clinical variability of intermediate phenotypes, and the rarity of the disorder all contribute to delayed recognition. These factors underscore the importance of maintaining a high index of suspicion and pursuing early metabolic and genetic testing in atypical pediatric presentations. Trial registration Not applicable.
2024-12-19 | Endothelial and neuronal engagement by AAV-BR1 gene therapy alleviates neurological symptoms and lipid deposition in a mouse model of Niemann-Pick type C2
Background: Patients with the genetic disorder Niemann-Pick type C2 disease (NP-C2) suffer from lysosomal accumulation of cholesterol causing both systemic and severe neurological symptoms. In a murine NP-C2 model, otherwise successful intravenous Niemann-Pick C2 protein (NPC2) replacement therapy fails to alleviate progressive neurodegeneration as infused NPC2 cannot cross the blood-brain barrier (BBB). Genetic modification of brain endothelial cells (BECs) is thought to enable secretion of recombinant proteins thereby overcoming the restrictions of the BBB. We hypothesized that an adeno-associated virus (AAV-BR1) encoding the Npc2gene could cure neurological symptoms in Npc2-/- mice through transduction of BECs, and possibly neurons via viral passage across the BBB. Methods: Six weeks old Npc2-/- mice were intravenously injected with the AAV-BR1-NPC2 vector. Composite phenotype scores and behavioral tests were assessed for the following six weeks and visually documented. Post-mortem analyses included gene expression analyses, verification of neurodegeneration in Purkinje cells, determination of NPC2 transduction in the CNS, assessment of neuroinflammation, quantification of gangliosides and co-detection of cholesterol with NPC2 in degenerating neurons. Results: Treatment with the AAV-BR1-NPC2 vector improved motor functions, reduced neocortical inflammation, and preserved Purkinje cells in most of the mice, referred to as high-responders. The vector exerted tropism for BECs and neurons resulting in a widespread NPC2 distribution in the brain with a concomitant reduction of cholesterol in adjacent neurons, presumably not transduced by the vector. Mass spectrometry imaging revealed distinct lipid alterations in the brains of Npc2-/- mice, with increased GM2 and GM3 ganglioside accumulation in the cerebellum and hippocampus. AAV-BR1-NPC2 treatment partially normalized these ganglioside distributions in high responders, including restoration of lipid profiles towards those of Npc2+/+ controls. Conclusion: The data suggests cross-correcting gene therapy to the brain via delivery of NPC2 from BECs and neurons.
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.
2022-05-12 | A novel strategy for deliveringNiemann‐Pick typeC2proteins across the blood–brain barrier using the brain endothelial‐specificAAV‐BR1virus
Abstract Treating central nervous system (CNS) diseases is complicated by the incapability of numerous therapeutics to cross the blood–brain barrier (BBB), mainly composed of brain endothelial cells (BECs). Genetically modifying BECs into protein factories that supply the CNS with recombinant proteins is a promising approach to overcome this hindrance, especially in genetic diseases, like Niemann Pick disease type C2 (NPC2), where both CNS and peripheral cells are affected. Here, we investigated the potential of the BEC‐specific adeno‐associated viral vector (AAV‐BR1) encoding NPC2 for expression and secretion from primary BECs cultured in an in vitro BBB model with mixed glial cells, and in healthy BALB/c mice. Transduced primary BECs had significantly increased NPC2 gene expression and secreted NPC2 after viral transduction, which significantly reversed cholesterol deposition in NPC2 deficient fibroblasts. Mice receiving an intravenous injection with AAV‐BR1‐NCP2‐eGFP were sacrificed 8 weeks later and examined for its biodistribution and transgene expression of eGFP and NPC2. AAV‐BR1‐NPC2‐eGFP was distributed mainly to the brain and lightly to the heart and lung, but did not label other organs including the liver. eGFP expression was primarily found in BECs throughout the brain but occasionally also in neurons suggesting transport of the vector across the BBB, a phenomenon also confirmed in vitro . NPC2 gene expression was up‐regulated in the brain, and recombinant NPC2 protein expression was observed in both transduced brain capillaries and neurons. Our findings show that AAV‐BR1 transduction of BECs is possible and that it may denote a promising strategy for future treatment of NPC2. image
proteins
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.
2025-10-03 | Lysosomal Storage Disorders
Abstract Lysosomes are intracellular organelles that are responsible for degrading and recycling macromolecules. Lysosomal diseases (LDs) are a group of rare inherited diseases caused by deleterious variants affecting genes that encode the lysosomal enzymes, their transporter or their cofactor. Among LDs that are associated with lung involvement and/or interstitial lung disease (ILD) acid sphingomyelinase deficiency [ASMD formerly called Niemann–Pick A, AB, and B diseases]) is the most common. An history of lower respiratory tract infections and exertional dyspnea are the most frequent respiratory manifestations. In ASMD, ILD is frequent and is usually associated with spleen and/or liver enlargement, low platelet count, and low level of high-density lipoprotein cholesterol. A restrictive lung functional pattern and a reduction in DLCO value are usually observed. Analysis of bronchoalveolar lavage fluid and lung biopsy showing foamy cells can orientate the diagnosis, based on the demonstration of an enzymatic deficiency in sphingomyelinase in the blood, associated with biallelic pathogenic variants of the SMPD1 gene. An enzyme replacement therapy (ERT), based on intravenous recombinant enzyme infusions (olipudase alfa), is available from 2021 with very encouraging results both in pediatric and adult patients affected with type B or AB. Olipudase alfa administration decreased liver and spleen volume, increased DLCO value and improved radiological lung involvement. Available enzyme replacement therapy supports an early diagnosis to implement therapy before any irreversible organ damage.
2021-09-24 | Apolipoprotein D-mediated preservation of lysosomal function promotes cell survival and delays motor impairment in Niemann-Pick type A disease.
Lysosomal Storage Diseases (LSD) are genetic diseases causing systemic and nervous system dysfunction. The glia-derived lipid binding protein Apolipoprotein D (ApoD) is required for lysosomal functional integrity in glial and neuronal cells, ensuring cell survival upon oxidative stress or injury. Here we test whether ApoD counteracts the pathogenic consequences of a LSD, Niemann Pick-type-A disease (NPA), where mutations in the acid sphingomyelinase gene result in sphingomyelin accumulation, lysosomal permeabilization and early-onset neurodegeneration. We performed a multivariable analysis of behavioral, cellular and molecular outputs in 12 and 24 week-old male and female NPA model mice, combined with ApoD loss-of-function mutation. Lack of ApoD in NPA mice accelerates cerebellar-dependent motor deficits, enhancing loss of Purkinje neurons. We studied ApoD expression in brain sections from a NPA patient and age-matched control, and the functional consequences of ApoD supplementation in primary human fibroblasts from two independent NPA patients and two control subjects. Cell viability, lipid peroxidation, and lysosomal functional integrity (pH, Cathepsin B activity, Galectin-3 exclusion) were examined. ApoD is endogenously overexpressed in NPA patients and NPA mouse brains and targeted to lysosomes of NPA patient cells, including Purkinje neurons and cultured fibroblasts. The accelerated lysosomal targeting of ApoD by oxidative stress is hindered in NPA fibroblasts, contributing to NPA lysosomes vulnerability. Exogenously added ApoD reduces NPA-prompted lysosomal permeabilization and alkalinization, reverts lipid peroxides accumulation, and significantly increases NPA cell survival. ApoD administered simultaneously to sphingomyelin overload results in complete rescue of cell survival. Our results reveal that ApoD protection of lysosomal integrity counteracts NPA pathology. ApoD supplementation could significantly delay not only the progression of NPA disease, but also of other LSDs through its beneficial effects in lysosomal functional maintenance.
2018-01-16 | Excess sphingomyelin disturbs ATG9A trafficking and autophagosome closure.
Sphingomyelin is an essential cellular lipid that traffics between plasma membrane and intracellular organelles until directed to lysosomes for SMPD1 (sphingomyelin phosphodiesterase 1)-mediated degradation. Inactivating mutations in the SMPD1 gene result in Niemann-Pick diseases type A and B characterized by sphingomyelin accumulation and severely disturbed tissue homeostasis. Here, we report that sphingomyelin overload disturbs the maturation and closure of autophagic membranes. Niemann-Pick type A patient fibroblasts and SMPD1-depleted cancer cells accumulate elongated and unclosed autophagic membranes as well as abnormally swollen autophagosomes in the absence of normal autophagosomes and autolysosomes. The immature autophagic membranes are rich in WIPI2, ATG16L1 and MAP1LC3B but display reduced association with ATG9A. Contrary to its normal trafficking between plasma membrane, intracellular organelles and autophagic membranes, ATG9A concentrates in transferrin receptor-positive juxtanuclear recycling endosomes in SMPD1-deficient cells. Supporting a causative role for ATG9A mistrafficking in the autophagy defect observed in SMPD1-deficient cells, ectopic ATG9A effectively reverts this phenotype. Exogenous C12-sphingomyelin induces a similar juxtanuclear accumulation of ATG9A and subsequent defect in the maturation of autophagic membranes in healthy cells while the main sphingomyelin metabolite, ceramide, fails to revert the autophagy defective phenotype in SMPD1-deficient cells. Juxtanuclear accumulation of ATG9A and defective autophagy are also evident in tissues of smpd1-deficient mice with a subsequent inability to cope with kidney ischemia-reperfusion stress. These data reveal sphingomyelin as an important regulator of ATG9A trafficking and maturation of early autophagic membranes.
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2023-04-10 | Sphingomyelin 16:0 is a therapeutic target for neuronal death in acid sphingomyelinase deficiency.
Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder caused by mutations in the SMPD1 gene encoding for the acid sphingomyelinase (ASM). While intravenous infusion of recombinant ASM is an effective treatment for the peripheral disease, the neurological complications of ASMD remain unaddressed. It has been shown that aberrantly high level of total brain sphingomyelin (SM) is a key pathological event leading to neurodegeneration. Using mice lacking ASM (ASMko), which mimic the disease, we here demonstrate that among the SM species, SM16:0 shows the highest accumulation and toxicity in ASMko neurons. By targeting lysosomes, SM16:0 causes permeabilization and exocytosis of these organelles and induces oxidative stress and cell death. We also show that genetic silencing of Ceramide Synthase 5, which is involved in SM16:0 synthesis and overexpressed in the ASMko brain, prevents disease phenotypes in ASMko cultured neurons and mice. The levels of SM16:0 in plasma also show a strong correlation with those in brain that is higher than in liver, even at early stages of the disease. These results identify SM16:0 both as a novel therapeutic target and potential biomarker of brain pathology in ASMD.
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Drug Discovery Landscape
2 orphan drug designations for Infantile neurovisceral acid sphingomyelinase deficiency, including 1 approved therapy.
2 orphan drug designations for Infantile neurovisceral acid sphingomyelinase deficiency, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Trans-Cinnamic Acid | proteins | FDA | — | Polaryx Therapeutics, Inc. |
olipudase alfa-rpcp [Xenpozyme] | proteins | FDA | Approved | Genzyme Corporation |
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