Neurofilaments SCA3

Neurofilaments as blood biomarkers of SCA3 progression in humans and mice

01.03.2019 bis 29.02.2020

Background and rationale
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common dominantly inherited form of degenerative ataxia. Its fatal course is marked by irreversible decline of motor control with dramatic impact on daily life, affecting patients and their families already in mid-life. Advances in the understanding of the toxic gain-of-function mechanisms underlying SCA3 neurodegeneration have opened a window for targeted molecular therapies. Particularly, interventions with antisense oligonucleotides (ASOs) targeting mutated ATXN3 show promising results in mitigating the molecular, pathological and behavioural disease-associated changes in SCA3 mouse models (McLoughlin et al., 2018, Ann. Neurol.). ASO treatments might even allow preventing the neurodegenerative process before the occurrence of clinical symptoms. Thus, to pave the way for upcoming translational trials of these promising therapies, easily accessible, objective and sensitive outcome parameters are urgently needed to track disease progression in both the presymptomatic and symptomatic stage of SCA3 disease. Such parameters will need validation in large human SCA3 cohorts and ideally also in SCA3 mouse models, as these allow biomaterial sampling, standardised phenotyping and neuropathological validation at multiple time points during both the presymptomatic and symptomatic disease stage.

Goal and key outcome
We here propose an innovative trans-species SCA3 biomarker study to establish peripheral blood biomarkers of disease onset and progression in both human disease and mouse models, and to validate them with respect to the underlying neuropathology both at the presymptomatic and symptomatic stage. To this end, we will combine a unique large cohort of SCA3 mutation-carriers in both the presymptomatic and symptomatic stage of the disease, aggregated across multiple countries, and a well-established 223Q SCA3 knock-in mouse model including both heterozygous and homozygous animals, thus allowing to investigate also mutation dosage effects. Our study fully serves the overarching objective of the National Ataxia Foundation to promote research to find a cure for ataxia, as it will establish and validate easily accessible, sensitive and reliable peripheral blood biomarkers paving the way for upcoming treatment trials in SCA3.