Background Neurofilament light protein (NfL) has emerged as a promising biomarker candidate. Detectable in CSF and blood, NfL correlates with HD severity and provides an ongoing measure of neuronal damage, suggesting multiple potential utilities: stratification and enrichment, as a prognostic biomarker, and as a safety biomarker.

Aims Evaluate NfL’s multiple utilities as a translational biomarker of HD using human cell models and patient biofluid data.

Methods Biofluid NfL was modelled in vitro using iPSC-derived medium spiny neurons from HD patients and controls. NfL release was quantified via immunoassay of the culture media, and pathophysiology was characterised using immunocytochemistry (ICC). Different therapeutic interventions were performed to assess safety biomarker utility. NfL natural history will be characterised throughout HD via retrospective analysis of patient biofluid from multiple observational cohorts (TRACK/TrackOn-HD, PREDICT-HD, HD-CSF, HD-YAS). NfL data will be collated and harmonised using conversion models for assay calibration and blood collection tube type (generated from a subcohort with matched LiHep, EDTA and CPT collections). NfL will be analysed in the resulting pan-study dataset across HD-ISS stages and against clinical and MRI outcomes using mixed-effects models.

Results In cell models, media NfL concentration correlated with neuronal damage, and NfL was detectable via ICC; further characterisation ongoing. In patient biofluids, NfL measurements were elevated in LiHep samples, and EDTA/CPT data were adjusted accordingly. Ongoing work focuses on completing the harmonisation pipeline and downstream analyses.

Conclusions Comprehensive evaluation of NfL’s multiple translational roles through utilisation of cell models and patient data could facilitate therapeutic development in HD.