Biomarker Validation in NPC1: Foundations for Clinical Trials and Regulatory Alignment

Abstract

Niemann–Pick Type C1 (NPC1) disease is a rare, autosomal recessive, neurovisceral lysosomal storage disorder caused by mutations in the NPC1. This condition leads to defective intracellular cholesterol and lipid trafficking, resulting in the accumulation of unesterified cholesterol and glycosphingolipids in late endosomes and lysosomes. Clinically, NPC1 manifests with a heterogeneous spectrum of progressive neurological symptoms, including ataxia, vertical supranuclear gaze palsy, dysarthria, cognitive decline, and dystonia, often accompanied by systemic signs such as hepatosplenomegaly and neonatal cholestasis. The age of neurological symptom onset, rather than age at diagnosis, better reflects disease severity and progression, as delays in diagnosis are common due to phenotypic variability and lack of awareness. Therapeutic development for NPC1 has been historically limited, with miglustat approved in some regions for off-label use and 2-hydroxypropyl-β-cyclodextrin currently under clinical investigation. Recent advances in disease understanding have prompted the development of pharmacodynamic, diagnostic, and prognostic biomarkers to support earlier diagnosis and monitor therapeutic efficacy. Dysregulation of cholesterol homeostasis, neuroinflammation, and neuronal loss have guided biomarker discovery, with promising candidates including 24(S)-hydroxycholesterol, neurofilament light chain, and bile acid derivatives such as 3β,5α,6β-trihydroxycholanic acid. Novel lipid biomarkers including N-palmitoyl-O-phosphocholine-serine and oxysterols such as 7-ketocholesterol and cholestane-3β,5α,6β-triol also show diagnostic value. Despite growing mechanistic insight and a robust pipeline of candidate biomarkers and therapies, NPC1 remains a life-limiting disease with significant diagnostic and therapeutic gaps. Ongoing clinical trials and translational research are essential to accelerate biomarker qualification and regulatory approval of disease-modifying treatments. A comprehensive, mechanistically driven approach that integrates molecular, biochemical, and clinical endpoints is key to advancing precision medicine for NPC1.