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

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.

Sodium and chloride channelopathies with myositis: coincidence or connection?

INTRODUCTION: A proximal myopathy develops in some patients with muscle channelopathies, but the causative molecular mechanisms are unknown. METHODS: We reviewed retrospectively all clinical and muscle biopsy findings of 3 patients with channelopathy and additional myositis. Direct DNA sequencing was performed. RESULTS: Pathogenic mutations were identified in each case. Biopsies demonstrated inflammatory infiltrates. CONCLUSIONS: Clinicians should consider muscle biopsy in channelopathy patients with severe myalgia and/or subacute weakness and accompanying elevated creatine kinase. Chance association of myositis and channelopathy is statistically unlikely. An alternative hypothesis suggests that inflammatory insults could contribute to myopathy in some patients.