Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3

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Science Translational Medicine  21 Oct 2020:
Vol. 12, Issue 566, eabb7086
DOI: 10.1126/scitranslmed.abb7086

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Detecting toxic protein

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the ATXN3 gene. Reducing the toxic polyQ ATXN3 protein might be an effective strategy for treating the disease; the identification of pharmacodynamic markers would facilitate the assessment of potential therapies. Prudencio et al. showed that the toxic protein could be detected in cerebrospinal fluid from patients, and could be used to assess treatment response. Moreover, the authors identified a single-nucleotide polymorphism in the ATXN3 gene associated with CAG-expanded alleles. The results could improve the development of therapies and the evaluation of treatment efficacy.


Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.

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