Biomarkers for NPC

How will investigators, clinicians and patients know if their therapeutic for the treatment of NPC is efficacious? In this blog post we will explore a few of the potential biomarkers that can be used to monitor disease progression in patients with Niemann Pick C.

24(S) hydroxycholesterol

Patients with Niemann Pick C classically present symptoms of neurodegeneration. Can a biomarker be captured that is indicative of neurodegeneration related to the altered cholesterol metabolism? 24S-HC is a cholesterol metabolite formed in the brain. The synthesis of 24S-HC cholesterol plays a role in maintaining cholesterol homeostasis in the brain, as excess cholesterol may be toxic. So 24S-HC is generated and secreted across the blood brain barrier. If there is increased cholesterol in the brain, then 24S-HC could be used a marker to determine if cholesterol levels have increased or decreased. For more detailed information check out the a human plasma study by Sidhu et al, for the validation of 24(S)-HC as an NPC biomarker.

cathepsin and lysozyme

It was shown that Niemann Pick C mouse models display inflammatory disease in the liver and other tissue. So could inflammatory markers be used as a way to monitor disease progression? Cathepsins are proteases that are activated in the low pH environment of the lysosome. They play a role in cell turnover and are implicated in neurodegenerative disease. Lysozyme is an enzyme that targets peptidoglycans of bacterial cell walls, protecting humans from pathogens. Alam et al validated both cathepsin and lysozyme as inflammatory markers for NPC in diseased mouse and human tissue. They did this by performing microarray analysis on tissue from diseased and cyclodextrin treated mice. Specifically, cathepsin activity is increased in neuronal and liver tissue of NPC mice. And post cyclodextrin treatment, the liver levels decrease. As for lysozyme, transcript levels in the brain of NPC mice are increased as well as plasma levels and decrease post cyclodextrin treatment.

lysosphingomyelin 509

This is a new biomarker established for the diagnosis of patients as described by Giese et al.   Patients were enrolled in biomarker study specifically for NPC. The plasma from these patients as well as healthy controls was analyzed using HPLC-MS/MS. NPC patients have higher values of this marker in their plasma as compared to carrier and healthy patient controls.


Pajares et al performed a biomarker study on healthy patients and patients with different lipid disorders. They found that cholestane-3β,5α,6β-triol levels are increased in NPC patients as well as in patients with cerebrotendinous xanthomatosis and lysosomal acid lipase deficiency.

Biomarkers are critical for early diagnosis as well as monitoring disease progression. And importantly, when there is a promising treatment for disease, biomarkers are required for both preclinical and clinical studies to help assess therapeutic efficacy.  If you want to learn more about biomarkers check out FDA’s Biomarker Qualification Program and this review on rare disease biomarker endpoints for use as primary endpoints.

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