What is Niemann-Pick Disease?

Niemann-Pick Disease (NPD) is an autosomal recessive inherited lysosomal storage disorder, also known as sphingomyelin-cholesterol lipidosis. Based on pathogenesis and clinical manifestations, NPD is primarily classified into two major categories: A/B type and C type.

A/B Type (Acid Sphingomyelinase Deficiency): Type A is the acute neurological form, typically presenting at 3-6 months after birth with hepatosplenomegaly, feeding difficulties, extreme emaciation, progressive intellectual and motor developmental regression. Approximately half of patients exhibit cherry-red spots in the fundus, and most die before 3-4 years of age. Type B is the non-neurological or visceral form, with later onset, primarily manifesting as hepatosplenomegaly, normal intelligence, and absence of neurological symptoms. Patients can survive into adulthood but often experience complications such as interstitial lung disease and thrombocytopenia.

C Type (Cholesterol Transport Disorder): The age of onset varies widely, ranging from the perinatal period to adulthood. Childhood and adolescent presentations include characteristic neurological symptoms such as vertical supranuclear gaze palsy, ataxia, dysarthria, cataplexy with laughter, and cognitive impairment.

The incidence of NPD-A/B type varies among different ethnic populations worldwide, ranging from approximately 1/250,000 to 1/44,960, while NPD-C type incidence ranges from 1/150,000 to 1/120,000. In Asian populations, the incidence is lower, with Type A being more common, accounting for approximately 85% of cases.

Pathogenesis

Niemann-Pick Disease A/B Type (NPD-A/B): Caused by mutations in the SMPD1 gene leading to acid sphingomyelinase (ASM) functional deficiency. This gene, located at 11p15.1-p15.4, encodes ASM, which is responsible for hydrolyzing sphingomyelin to ceramide and phosphocholine in lysosomes. When SMPD1 mutations occur, ASM activity is significantly reduced (Type A <5%, Type B 5%-10%), resulting in impaired sphingomyelin degradation.

Enzyme activity deficiency leads to abnormal accumulation of sphingomyelin in the mononuclear phagocyte system and brain tissue, forming characteristic foam cells (Niemann-Pick cells). Sphingomyelin is a crucial component of cell membranes and subcellular organelles, and its abnormal accumulation causes multi-organ damage: hepatosplenomegaly in the liver, spleen, and bone marrow; interstitial lung disease in the lungs; and neuronal dysfunction and progressive neurodegeneration in brain tissue. Additionally, ASM deficiency reduces ceramide production, affecting cell signaling transduction and apoptosis regulation, further exacerbating disease progression.

Niemann-Pick Disease C Type (NPC): The core pathogenesis stems from mutations in the NPC1 or NPC2 genes, leading to impaired transport of cholesterol and sphingolipids within lysosomes. Under normal physiological conditions, the NPC2 protein delivers intraluminal cholesterol to the membrane protein NPC1, which completes the efflux process. Functional loss results in abnormal lipid accumulation in lysosomes while simultaneously causing cholesterol depletion in cellular compartments such as the endoplasmic reticulum.

Image Source The pathogenesis of Niemann-Pick type C disease: a role for autophagy?

 

This lipid transport disorder triggers abnormal activation of the autophagy pathway. Accumulated sphingolipids (such as ceramide) in lysosomes activate the class III PI3K/Beclin-1 complex, inducing autophagy in an mTOR-independent manner, manifested by increased conversion of LC3-I to LC3-II and massive formation of autophagosomes. However, the fusion efficiency between autophagosomes and lipid-overloaded, functionally impaired lysosomes is low, leading to autophagic flux blockade, impaired autophagosome clearance, and the formation of "autophagic stress."

Autophagy exhibits a dual role in NPC: initially serving as an adaptive response attempting to clear toxic lipids; but persistent autophagic flux blockade leads to accumulation of undegraded substrates, which themselves become cellular stressors, ultimately activating apoptotic pathways and causing selective neuronal death (such as Purkinje cells), constituting the core mechanism of NPC neurodegeneration.
 

Image Source The pathogenesis of Niemann-Pick type C disease: a role for autophagy?
 

Gene Therapy

Recombinant Adeno-Associated Virus (rAAV) Vector Therapy: For Niemann-Pick Disease Type C (NPC) caused by NPC1 or NPC2 gene mutations, a novel truncated NPC1 promoter has demonstrated superior expression efficiency compared to commonly used CBA or Synapsin promoters in mouse models, significantly improving survival, motor function, and neuropathology. Administration routes include intracerebroventricular injection or intravenous injection during the neonatal period, with AAV9 serotype widely used due to its excellent central nervous system penetration. However, high-dose viral vectors still carry potential genotoxicity risks.

Plasmid-Based Gene Delivery Systems: For NPC1 disease mouse models, "Trojan horse" liposomes targeting the transferrin receptor can encapsulate large plasmids containing the PDGF-B promoter and human NPC1 cDNA. Intravenous injection delivers the gene to mouse brain, liver, spleen, and other tissues, with observed reductions in intracellular lipid accumulation and improvements in astrocyte proliferation.

Mouse Models

NPC1-/- Mice: A classic and widely used NPC1 disease model. Homozygous mice exhibit typical and severe systemic pathology due to complete loss of NPC1 protein function. Core phenotypes include significant motor dysfunction, severe neurodegenerative pathological changes, and prominent visceral organ lesions (manifested as massive cholesterol and sphingolipid accumulation in liver and spleen, leading to organ enlargement and numerous vacuolated foam cells visible in tissue sections).

NPC1nmf164 Mice: An important NPC1 gene mutation model with overall phenotype highly similar to the NPC1-/- model, also exhibiting shortened lifespan, progressive neurological dysfunction, and characteristic neuropathological features. This model is often specifically used for in-depth evaluation of therapeutic strategies' effects on specific neuropathological indicators.

NPC2-/- Mice: Simulates human Niemann-Pick Disease Type C2 caused by NPC2 gene functional loss. NPC2-/- mice exhibit systemic phenotypes highly similar to NPC1-/- mice, serving as a key tool for validating the broad-spectrum efficacy of therapeutic strategies against NPC disease and for in-depth study of the complete molecular mechanism of cholesterol transport from lysosomal lumen to membrane.

MingCeler Biotech Supports Gene Therapy

Gene therapy offers hope for rare diseases, but its development and validation critically depend on animal model support. MingCeler Biotech has developed multiple rare disease mouse models using its proprietary TurboMice™ technology. The TurboMice™ platform overcomes technical challenges associated with long mouse model generation cycles and low success rates for complex models, enabling editing at virtually any target gene locus and producing complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as 2 months.

MingCeler Biotech can customize various NPD mouse models according to client needs, including NPC1-/- mice, NPC1nmf164 mice, NPC2-/- mice, and others. We welcome inquiries from researchers!
 

References:

[1] https://www.ncbi.nlm.nih.gov/books/NBK556129/

[2] Schuchman EH. The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease. J Inherit Metab Dis. 2007 Oct;30(5):654-63. doi: 10.1007/s10545-007-0632-9. Epub 2007 Jul 12. PMID: 17632693.

[3] Pacheco CD, Lieberman AP. The pathogenesis of Niemann-Pick type C disease: a role for autophagy? Expert Rev Mol Med. 2008 Sep 10;10:e26. doi: 10.1017/S146239940800080X. PMID: 18782459; PMCID: PMC2662713.

[4] Alobaidy H. Recent advances in the diagnosis and treatment of niemann-pick disease type C in children: a guide to early diagnosis for the general pediatrician. Int J Pediatr. 2015;2015:816593. doi: 10.1155/2015/816593. Epub 2015 Feb 16. PMID: 25784942; PMCID: PMC4345273.

[5] Hughes MP, Nelvagal HR, Coombe-Tennant O, Smith D, Smith C, Massaro G, Poupon-Bejuit L, Platt FM, Rahim AA. A Novel Small NPC1 Promoter Enhances AAV-Mediated Gene Therapy in Mouse Models of Niemann-Pick Type C1 Disease. Cells. 2023 Jun 13;12(12):1619. doi: 10.3390/cells12121619. PMID: 37371089; PMCID: PMC10296851.

[6] Jiang, D., Lee, H. & Pardridge, W.M. Plasmid DNA gene therapy of the Niemann-Pick C1 mouse with transferrin receptor-targeted Trojan horse liposomes. Sci Rep 10, 13334 (2020). https://doi.org/10.1038/s41598-020-70290-w

[7] El-Mezayen M, Tawfik AM, Hadhoud AM, Gerges VM, Afify MH. Exploring the boundaries of Niemann-Pick disease type A/B: a report of a case and review of literature. Mol Cell Pediatr. 2025 Nov 10;12(1):18. doi: 10.1186/s40348-025-00206-z. PMID: 41208004; PMCID: PMC12597853.

Special Statement: This article is from the official WeChat account of MingCeler Biotech. Personal sharing is welcome. Media or institutions are prohibited from reprinting to other platforms without authorization. For reprint permission or other inquiries, please contact us via the official account backend or at sales@mingceler.com.

Disclaimer: Some materials are sourced from the internet. Contact us for removal if infringement is found. This article is for informational purposes only and does not constitute treatment recommendations. The views expressed do not represent the official stance of MingCeler Biotech. For treatment guidance, please consult a qualified healthcare professional at a formal medical institution.