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
154 drug discovery papers about Infantile neurovisceral acid sphingomyelinase deficiency, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
154 drug discovery papers about Infantile neurovisceral acid sphingomyelinase deficiency, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
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.
2026-04-28 | 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.
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.
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.
2026-04-28 | 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.
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.
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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 | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Trans-Cinnamic Acid | proteins | FDA | 2020-11-24 | — | Polaryx Therapeutics, Inc. |
olipudase alfa-rpcp [Xenpozyme] | proteins | FDA | 2000-08-03 | 2022-08-31 | Genzyme Corporation |
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