Whether you are a family member, researcher, clinician, or an individual with ties to therapeutic development — the sheer amount of information related to rare disease, and even NPC disease specifically, can be simply overwhelming.
There already exists a number of helpful websites and publications along with an abundance of expertise in this field so our goal with the NPC Therapy Accelerator is not to reinvent the wheel… rather we want to provide a simple description of the topic and point you to trustworthy sources containing relevant information.
Research Tools

NPC Animal Models

The NPC community is fortunate to have a wide range of model organisms to better understand the disease and in which to test potential therapeutics. These models range from yeast to feline and are nicely summarized in the FogCK et al 2019 review.

NPC1 Feline Model

This NPC1 cat model carries a point mutation (C955S) and recapitulates a juvenile onset NPC disease. SomersKL et al 2003 describes the mutation while numerous later publications provide evidence for this models usefulness in testing therapeutic agents (e.g. ViteCH et al 2015).

NPC Murine Models

NPC murine models are numerous. The most utilized models are listed below, although the relative ease of manipulating mouse genetics allows rapid generation of new models, typically with a specific purpose/scientific question in mind. Many of these models are available at the Jackson Laboratory (jax.org/mouse-search?searchTerm=NPC1). The following list does not provide all mouse models and interested parties are encouraged to explore the Jackson Laboratory website and the numerous publications on different Npc1 models.

    1. Npc1m1Nmice(BALB/cNctr-Npc1m1n/J, aka Npc1nih; https://www.jax.org/strain/003092) are the most commonly used model and provide a rapid onset and disease progression similar to the early infantile onset in patients. These mice harbor a spontaneous mutation in which an insertion leads to truncation of 11 of the 13 transmembrane domains.
    2. Npc1m1Nmice(B6.C-Npc1m1n/GarvJ, aka C57BL/6J Npc1m1N; https://www.jax.org/strain/030097) are similar to the Npc1m1Nmice but on a Bl/6 background, which leads to an earlier onset of disease and more severe phenotype.
    3. Npc1tm1Dsomice(B6.129-Npc1tm1Dso/J, aka Npc1I1061T; https://www.jax.org/strain/027704) were generated with a point mutation (I1061T) which is the most commonly occurring mutation in NPC1 patients. These mice present with a slightly delayed, though still rapidly progressing, disease course. PraggastisM et al 2015(PMID:26019327, DOI: 10.1523/JNEUROSCI.4173-14.2015) characterizes this model.
    4. Npc1nmf164mice(C57BL/6J-Npc1nmf164/J;https://www.jax.org/strain/004817) have a point mutation (D1005G) and the resulting phenotype is slightly delayed compared to the Npc1m1Nmice, likely because residual protein levels remain.
    5. Npc1spmmice(C57BLKS/J-Npc1spm/J;https://www.jax.org/strain/002760) result from a spontaneous mutation which leads to frameshift and premature stop codon. Disease progression is similar to the Npc1m1Nmodel albeit modestly longer lifespan even in the presence of faster Purkinje neuron loss in the cerebellum.
    6. Npc2-/-mice() were generated by targeted genetic disruption. This model shares the phenotype and pathological manifestations observed in the Npc1m1Nmodel, albeit with a slightly protracted disease course. SleatDE et al 2004 (PMID: 15071184, DOI: 10.1073/pnas.0308456101) provide characterization of this model.

      NPC1 Zebrafish (Danio rerio)

      The zebrafish offers an in vivo model suitable for high throughput screening. Two independent labs have generated NPC1 zebrafish lines using CRISPR/Cas9-mediated gene targeting.

      • PMID: 29897878, DOI: 10.1515/hsz-2018-0118 (LinY et al, 2018)
      • PMID: 30135069, DOI: 10.1242/dmm.034165 (TsengWC et al, 2018)

      NPC Fruit Flies (Drosophila melanogaster)

      The flies are less frequently utilized in studies, but are available and have their own merits.

      NPC1 Roundworm (Caenorhabditis elegans)

      The NPC1 roundworm models have also been characterized, but again, their use in studies is limited.

      The world of “-omics”

      By adding -omics to the end of a discipline in the biological sciences, you refer to a high throughput way to measure biological molecules within an organism. General descriptions of several different “-omics” are listed below along with resources to continue learning and some investigators in the NPC community whose focus lies therein.


      Genomics is the study of a genome, or all gene within an organism. The National Human Genome Research Institute provides a nice overview of genomics: https://www.genome.gov/about-genomics/fact-sheets/A-Brief-Guide-to-Genomics

      Recent NPC Genomic Publications


      Lipidomics queries the multitude of different lipids within an organism, or the lipidome. Mass spectrometry, nuclear magnetic resonance spectroscopy, fluorescence spectroscopy, and other techniques are employed in lipidomics.

      Recent Publications:


      Metabolomics involves the study of small molecules produced during metabolism, aka metabolites, in a biological system. Frequently used techniques in this field are mass spectrometry and NMR spectroscopy. Washington University in St. Louis has a well-respected Metabolomics Facility where much of the pioneering work in biomarker development occurred. The group, led by Xuntian Jiang at WashU, is intimately familiar with NPC disease. https://research.wustl.edu/core-facilities/metabolomics-facility/In addition to metabolomics, this core also performs lipidomic analyses.

      Recent Publications

    1. Percival et al 2020
    2. Pugach et al 2019 
    3. Proteomics

      Proteomics focuses on the proteome and their functions within an organism. The proteome consists of all proteins in the organism. Important technologies employed in proteomics are protein purification and mass spectrometry. Two well-known NPC investigators have focused their careers on proteomics: Drs. William Balch (Scripps Research Institute – https://www.scripps.edu/balch/) and Stephanie Cologna (University of Illinois at Chicago – https://chem.uic.edu/profiles/stephanie-m-cologna/).

      Recent Publications


      Transcriptomics investigates the transcriptome, or broadly speaking, the RNA transcripts that are produced from an organism’s DNA. A commonly used technology in transcriptomics is microarray analysis.

      Recent Publications

      NPC Biomarkers & Disease Progression Analysis

      As the NPC community quickly came to realize, biomarkers play a crucial role in the development of therapeutics and understanding the disease process. Biomarkers are defined as substances or characteristics in an organism that can be measured and, in our case, relate to NPC disease. The FDA provides a succinct explanation of the importance of biomarkers in clinical trials. View transcript ›

      NPC Severity Score

      The NPC Clinical severity score is a linear scale that quantifies the major symptoms of NPC disease and is utilized to quantify disease progression. The scale includes clinical signs and symptoms in nine major categories; ambulation, cognition, eye movement, fine motor, hearing, memory, seizures, speech, swallowing, and eight minor categories; auditory brainstem response, behavior, gelastic cataplexy, hyperreflexia, incontinence, narcolepsy, psychiatric, respiratory problems.  The scale is the primary method used to evaluate disease progression in patients. Other information for disease progression include: full scale IQ, verbal IQ, and non-verbal IQ.

      Recent Publications

      Annual Severity Increment Score (ASIS)

      ASIS measures rate of disease progression and is stable over several years and can be used to stratify patients for clinical trials. It achieves greater homogeneity of the study cohort relative to age-based inclusion and provides an evidence-based approach for establishing inclusion/exclusion criteria.

      Recent Publications

      Active Biomarker Projects

      • Calbindin D is elevated in NPC1 cats and normalizes after treatment with2-hydroxypropyl-b-cyclodextrin.  Additionally, analysis of CFS from patients with NPC disease were significantly higher than patients that were unaffected. (Bradbury et al 2016) 
      • FABP3 showed decreased expression in CSF in miglustat treated groups vs. untreated. Additionally, FABP3 levels decreased in patients when treated 2-hydroxypropyl-b-cyclodextrin vs. untreated. (Ory et al 2017) 
      • GPNMB was shown to be upregulated in NPC mice and patients (Bradbury et al 2016) .  It is now being investigated as part of a multi-omic approach to address the genetic architecture of NPC1 disease. The Pavan group completed a transcriptome analysis using 43 primary NPC1 patient-derived fibroblasts from an NIH-cohort study where extensive clinical data was obtained regarding the natural history of the disease. Initial transcriptome analysis of this dataset demonstrated a set of 107 genes that were significantly upregulated in patient samples and subsequently downregulated in response to 2-hydroxypropyl-b-cyclodextrin treatment.  From this, screen the Pavan group identified GPNMB, glycoprotein nonmetastatic melanoma protein B also known as DC-Hil/Osteoactivin. They also demonstrated that it is associated with lysosomal dysfunction in the context of NPC disease in a mouse model.
      • Previous studies have shown that abnormal accumulation and recycling of glycosphingolipids, glycoproteins, and oligosaccharides were well established in NPC disease. Using targeted metabolomic screening, they found that six complex oligosaccharides were significantly elevated in cerebral spinal fluid (CSF) from NPC1 patients.
      • Please submit additional ongoing projects to Sean Kassen.

      Additional Potential Biomarkers

      Other Potential Biomarkersthat have been identified but have yet to show their effectiveness as a reliable biomarker:

      • Tau protein
      • glutathione S-transferase
      • superoxide dismutase
      • fatty acid binding protein 3
      • interleukin (IL)-3
      • chemokine ligand 5,
      • IL-16,
      • chemokine ligand 3
      • galectin-3
      • cathepsin D
      • lipids including monohexosylceramides ceramides, sphingoid bases, GM1 and GM3 gangliosides
      • 24(S)-HC