Evaluation of the landscape of pharmacodynamic biomarkers in Niemann-Pick Disease Type C (NPC)

Abstract

Niemann-Pick disease type C (NPC) is an autosomal recessive, progressive disorder resulting from variants in NPC1 or NPC2 that leads to the accumulation of cholesterol and other lipids in late endosomes and lysosomes. The clinical manifestations of the disease vary by age of onset, and severity is often characterized by neurological involvement. To date, no disease-modifying therapy has been approved by the United States Food and Drug Administration (FDA) and treatment is typically supportive. The lack of robust biomarkers contributes to challenges associated with disease monitoring and quantifying treatment response. In recent years, advancements in detection methods have facilitated the identification of biomarkers in plasma and cerebral spinal fluid from patients with NPC, namely calbindin D, neurofilament light chain, 24(S)hydroxycholesterol, cholestane-triol, trihydroxycholanic acid glycinate, amyloid-β, total and phosphorylated tau, and N-palmitoyl-O-phosphocholine-serine. These biomarkers have been used to support several clinical trials as pharmacodynamic endpoints. Despite the significant advancements in laboratory techniques, translation of those advancements has lagged, and it remains unclear which biomarkers correlate with disease severity and progression, or which biomarkers could inform treatment response. In this review, we assess the landscape of biomarkers currently proposed to guide disease monitoring or indicate treatment response in patients with NPC.

Keywords: Biomarkers; Drug development; Niemann Pick disease type C; Pharmacodynamics; Rare disease.

Fig. 1

Potential plasma and CSF biomarkers for neurodegeneration in Niemann-Pick disease type C (NPC). (A) This figure depicts a schematic of healthy and NPC affected brain where neurofilament light chain (NfL), calbindin D, c-triol (cholestane-3β, 5a, 6β-triol), and amyloid-β (Aβ) are elevated in the cerebral spinal fluid (CSF) and 24(S)-hydroxycholesterol is reduced in the CSF. Similar trends in biomarkers are seen in plasma. (B) In NPC, neurons may have neurofibrillary tangles of total and phosphorylated tau in the cell body of the neuron and are shown in dark red and purple. In the extracellular space, soluble and insoluble amyloid-β (Aβ) aggregates near the dendrites. Upon axonal injury, the highly expressed NfL in myelinated axons is leaked out into the interstitial fluid of the brain and in the CSF. Due to abberant cholesterol trafficking, conversion to 24(s)hydroxycholesterol is reduced due to a low supply of cholesterol as a substrate. Lastly, calbindin D may become elevated in the soma and intitial dendritic segments of the neuron potentially due to loss of cell loss. Created with BioRender.com