Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice.

Christian Barro,Mafalda Raposo,Maria Rakowicz,Kathrin Reetz,Magda M. Santana ,Kathrin Brockmann,Matthis Synofzik,Jeroen J. De Vries ,Luís Pereira De Almeida ,Jeannette Hübener‐Schmid,Alexandra Dürr ,Héctor García-Moreno ,Manuela Lima,Eva Haas,Béla Melegh ,Heike Jacobi,Judith van Gaalen,László Balikó ,Alessandro Filla,Jennifer Faber,Marcella Masciullo,Elke Stransky,Jens Kuhle,Paola Giunti,Manuela Neumann,Lüdger Schöls ,Thomas Klockgether,Bart P. Van De Warrenburg ,Stephan A. Kaeser ,Rebecca Schüle,Christian Deuschle,Jon Infante,Jörg B. Schulz ,Andreas Jeromin,Holger Hengel,Carlo Wilke

doi:10.15252/emmm.201911803

Abstract

With molecular treatments coming into reach for spinocerebellar ataxia type 3 (SCA3), easily accessible, cross‐species validated biomarkers for human and preclinical trials are warranted, particularly for the preataxic disease stage. We assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in ataxic and preataxic subjects of two independent multicentric SCA3 cohorts and in a SCA3 knock‐in mouse model. Ataxic SCA3 subjects showed increased levels of both NfL and pNfH. In preataxic subjects, NfL levels increased with proximity to the individual expected onset of ataxia, with significant NfL elevations already 7.5 years before onset. Cross‐sectional NfL levels correlated with both disease severity and longitudinal disease progression. Blood NfL and pNfH increases in human SCA3 were each paralleled by similar changes in SCA3 knock‐in mice, here also starting already at the presymptomatic stage, closely following ataxin‐3 aggregation and preceding Purkinje cell loss in the brain. Blood neurofilaments, particularly NfL, might thus provide easily accessible, cross‐species validated biomarkers in both ataxic and preataxic SCA3, associated with earliest neuropathological changes, and serve as progression, proximity‐to‐onset and, potentially, treatment‐response markers in both human and preclinical SCA3 trials.

Highlights

Spinocerebellar ataxia type 3 (SCA3), known as Machado– Joseph disease, is the most common dominantly inherited form of degenerative ataxia, caused by an expanded CAG repeat in the ATXN3 gene and marked by irreversible decline in motor function already in mid-life (Costa Mdo & Paulson, 2012; Rub et al, 2013)
To pave the way for upcoming treatment trials, accessible surrogate biomarkers are highly warranted in SCA3 for both human and preclinical trials
For preparing upcoming treatment trials, the biomarker value of neurofilament light (NfL) levels might lie in their potential as disease severity, progression and stratification biomarker, or—in terms of the Biomarker Qualification Program of the Food and Drug Administration (FDA)—in their potential as monitoring, prognostic, response and/or safety biomarker for SCA3 drug development

Summary

Introduction

Spinocerebellar ataxia type 3 (SCA3), known as Machado– Joseph disease, is the most common dominantly inherited form of degenerative ataxia, caused by an expanded CAG repeat in the ATXN3 gene and marked by irreversible decline in motor function already in mid-life (Costa Mdo & Paulson, 2012; Rub et al, 2013). Interventions with antisense oligonucleotides (ASOs) targeting mutated ATXN3 show promising results in mitigating the molecular, pathological and behavioural disease-associated changes in a SCA3 mouse model (McLoughlin et al, 2018). To pave the way for upcoming trials of these promising therapies, accessible, objective and sensitive outcome parameters are urgently needed to track disease progression in both the preataxic and ataxic stage of SCA3 disease. Such parameters require validation in large human SCA3 cohorts with standardised phenotyping and in SCA3 mouse models, as mouse models allow comprehensive neuropathological validation and preclinical treatment trials, even already during the presymptomatic stage

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