Now that we’ve completed our screen in all of our invertebrate models of Niemann Pick Type C (NPC) disease, it’s time for us to switch gears to the higher models of NPC. We are in the process of moving our validated screen hits for additional testing in a mouse model of NPC. So, this is a great juncture to introduce the mouse models that have been developed towards the study of NPC.

Mice are incredible models for the study of human diseases. They are slower, perhaps, to establish disease models of, and more cost and effort intensive, when it comes to biomedical studies. But, they are indispensible to the preclinical phase of therapeutics validation. And really, we’ve come a long way in the development of genetically engineered murine models compared to three decades ago.  The early mutant models in mice, even NPC, arose either as natural discoveries or through mass mutagenesis experiments!

One of the first mouse models of NPC, named as NPC1m1n (or NPC1nih) was first described by Pentchev et al in the 1980’s. In a series of successive studies, this model was found to store cholesterol in an aberrant manner by Morris et al., Shio et al. and Bhuvaneswaran et al. This mouse line originally resulted from a spontaneous mutation- a retroposon (repetitive DNA fragments that insert in chromosomes after they are reverse transcribed from RNA) inserted 1100bp of DNA and deleted 800bp of the NPC1 gene. This caused a frameshift, resulting in a ‘knock out’ of the NPC1 gene. Mice with this mutation show early-onset, rapid progression of NPC disease, evinced as slowed growth early on. Behaviorally, mice show an array of motor impairment phenotypes that can be studied by standard behavioral assays- think rotarod, balance beam and open field locomotor assays. These mice also show cognitive problems in learning and recall assays. This mouse model is commonly used since it displays the most severe form of NPC disease, displaying mortality between 80-90 days.

A second model of NPC was described around the same time as the first NPC1nih model, it is referred to as the NPC1spm model. It showed many phenotypic similarities to the NPC1nih mutant mouse model. This also arose due to a spontaneous mutation that was later mapped to the same gene. The disease syndrome caused by this gene has been diagnosed as analogous to NPC in humans. Mice with this defective mutation begin to lose weight and show tremor and ataxia from about seven weeks of age. Liver and spleen are enlarged and purkinje cells in the cerebellum are severely depleted. Sphingomyelin and cholesterols are elevated in the liver and the spleen, although the brain does not show obvious changes in lipid concentrations.

A more recent model of NPC was publicized in 2012. This model was generated by ENU mutagenesis of C57BL/6J strain of mice at the Jackson laboratory. This model, commonly referred to as NPC1nmf164, bears a point mutation in the NPC1 gene corresponding to a single amino acid change (D1005G). This point mutation results in normal levels of NPC mRNA but dramatically low levels of NPC protein. Thus, the partial functional loss of the protein results in a less severe manifestation of the disease. The nmf164 phenotype has a delayed onset and displays age dependent ataxia and shortened lifespan (112-120 days). However, behavioral deficits associated with motor skills in the NPC1nmf164 mice were less severe and appeared later in life compared to the NPCnih mice. Biochemically, this model shows progressive accumulation of sphingomyelin and glycosphingolipids in the liver and spleen and abnormal cholesterol levels. In the brain, loss of cerebellar Purkinje cells, abnormal astrocyte and microglial cell activation are also seen. It is important to note that while, phenotypically, this mouse model exhibits a less severe form of NPC, it is associated with a mutation that has not been found in humans with NPC. That said, the 1005 locus is in a cysteine-rich region of the NPC protein where numerous point mutations associated with human NPC disease are found.

The three models that have been described above pertain to zero to low levels of functional NPC protein. As previously mentioned in our blog, the incidence of NPC in humans takes many forms, associated with mutations in the NPC gene. These mutations involve gene truncations, early terminations and most commonly, point mutations. One of the most common point mutations associated with NPC is an isoleucine to threonine mutation at the 1061 position, referred to as the I1061T variant. This mutation results in improper folding of the full length protein. Such misfolded proteins then display poor endoplasmic reticulum (ER) stability, preventing trafficking for use in physiological processes. In theory, drugs that stabilize the misfolded protein could be therapeutically viable, as the stabilized protein could retain function. Until recently it was difficult to test this theory in a murine model of the point mutational variant of the disease.

However, earlier this year, the Ory group successfully generated a mouse model with an I1061T mutation in the NPC gene. When compared to the NPC1nih mouse strain, the point mutant displays a less severe, delayed form of the NPC disease. Reported differences include reduced weight loss, decreased motor coordination and premature death. At the histophatological level, purkinje neuron death and lipid storage are also reduced compared to the null mutant. The mutant protein isolated from these mice also has a reduced half-life in vivo consistent with the idea of a misfolded protein that is rapidly degraded in the ER.

Most of these mouse models (and really several more) can be found at Jackson Labs, a non-profit biomedical research institution that serves as the repository of more than 7000 strains of genetically defined mice, generated by researchers all over.

So, how does this help us? As I mentioned before, we’re in the process of advancing our promising chemical compounds into mouse models of NPC. We’ve selected a model from the above list and are in the process of conducting our study on them. Mouse studies are labor intensive and take a few months to complete, particularly when one studies multiple endpoints for a given disease. Thus, it will be a few months before we know the results of our study. While we wait with bated breaths, watch this space for new developments!



Loftus, S.K., Morris, J.A., Carstea, E.D., Gu, J.Z., Cummings, C., Brown, A., Ellison, J., Ohno, K., Rosenfeld, M.A., Tagle, D.A., Pentchev, P.G. and Pavan, W.J. (1997) Murine model of Niemann–Pick C disease: mutation in a cholesterol homeostasis gene. Science, 277, 232–235.

Miyawaki, S., Mitsouka, S., Sakiyama, T. and Kitagawa, T. (1982) Sphingomyelinosis, a new mutation in the mouse. A model of Niemann– Pick disease in humans. J. Hered., 73, 257–263.

Pentchev, P.G., Gal, A.E., Booth, A.D., Omodeo-Sale, F., Fouks, J., Neumeyer, B.A., Quirk, J.M., Dawson, G. and Brady, R.O. (1980) A lysosomal storage disorder in mice characterized by a dual deficiency of sphingomyelinase and glucocerebrosidase. Biochim. Biophys. Acta, 619, 669–679.

Morris, M.D., Bhuvaneswaran, C., Shio, H. and Fowler, S. (1982) Lysosome lipid storage in NCTR-BALBc mice. I. Description of the disease and genetics. Am. J. Pathol., 108, 140–149.

Shio, H., Fowler, S., Bhuvaneswaran, C. and Morris, M.D. (1982) Lysosome lipid storage disorder in NCTR-BALB/c mice. II. Morphologic and cytochemical studies. Am. J. Pathol., 108, 150–159.

Bhuvaneswaran, C., Morris, M.D., Shio, H. and Fowler, S. (1982) Lysosome lipid storage disorder in NCTR-BALB/c mice. III. Isolation and analysis of storage inclusions from liver. Am. J. Pathol., 108, 160–170.

Maue RA, Burgess RW, Wang B, Wooley CM, Sebrun KL, Varnier MT, Rogers MA, Chang CC, Chang TY, Harris BT, Graber DJ, Penatti CA, Porter DM, Szwergold BS, Henderson LP, Totenhagen JW, Trouard TP, Borbon IA, Erickson RP., (2012) A novel mouse model of Niemann-Pick type C disease carrying a D1005G-Npc1 mutation comparable to commonly observed human mutations.Hum Mol Genet., 21(4):730-50

Praggastis M, Tortelli B, Zhang J, Fuiwara H, Sidhu R, Chacko A, Chen Z, Chung C, Lieberman AP, Sikora J, Davidson C, Walkley SU, Pipalia NH, Maxfield FR, Schaffer JE, Ory DS, (2015), A murine Niemann-Pick C1 I1061T knock-in model recapitulates the pathological features of the most prevalent human disease allele. J Neurosci 35(21):8091-106.


Note: What I describe above are the seminal mouse models of NPC. Numerous genetic variations/derivatives of these have been generated (i.e. transgenics, different background strains etc.). For these, one can refer to the more comprehensive Jackson Labs website



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