Spinocerebellar ataxias: prospects and challenges for therapy development

Abstract

The spinocerebellar ataxias (SCAs) comprise more than 40 autosomal dominant neurodegenerative disorders that present principally with progressive ataxia. Within the past few years, studies of pathogenic mechanisms in the SCAs have led to the development of promising therapeutic strategies, especially for SCAs caused by polyglutamine-coding CAG repeats. Nucleotide-based gene-silencing approaches that target the first steps in the pathogenic cascade are one promising approach not only for polyglutamine SCAs but also for the many other SCAs caused by toxic mutant proteins or RNA. For these and other emerging therapeutic strategies, well-coordinated preparation is needed for fruitful clinical trials. To accomplish this goal, investigators from the United States and Europe are now collaborating to share data from their respective SCA cohorts. Increased knowledge of the natural history of SCAs, including of the premanifest and early symptomatic stages of disease, will improve the prospects for success in clinical trials of disease-modifying drugs. In addition, investigators are seeking validated clinical outcome measures that demonstrate responsiveness to changes in SCA populations. Findings suggest that MRI and magnetic resonance spectroscopy biomarkers will provide objective biological readouts of disease activity and progression, but more work is needed to establish disease-specific biomarkers that track target engagement in therapeutic trials. Together, these efforts suggest that the development of successful therapies for one or more SCAs is not far away.

Small heat shock proteins in neurodegenerative diseases

“…Spinocerebellar ataxias are a large group of neurodegenerative disorders of which the most prevalent ones are caused by the expansion of a glutamine-encoding CAG repeat in the respective genes (Paulson et al 2017). Their inheritance pattern is mostly autosomal dominant and the repeat size is linked to the disease penetrance (Ashizawa et al 2018). Patients typically present with gait imbalance associated with limb incoordination and problems with gross and fine motor skills.…”

Novel SCA19/22‐associated KCND3 mutations disrupt human K V 4.3 protein biosynthesis and channel gating

“…Despite the implementation of several clinical trials based on mechanistic studies of the pathogenesis of SCA, currently there is no specific medication approved for treating SCA patients (Ashizawa, Oz, & Paulson, 2018). Therapeutic approaches targeting voltagegated K + channels have been implicated in the treatment for cancer, arrhythmia, multiple sclerosis, and epilepsy (Wulff, Castle, & Pardo, 2009).…”

Towards ecologically valid biomarkers: real-life gait assessment in cerebellar ataxia

“…It has been shown in laboratory-based assessments that measures of spatial and temporal movement variability allow distinctively to capture and characterize the specificities of ataxic gait [3][4][5][6][7][8][9][10] . Moreover, they allow to quantify disease severity even at preclinical stages of DCA 11,12 and to capture treatment-induced improvements in a fine-grained fashion [13][14][15] , thus suggesting a high potential as both progression and treatment response parameters in the upcoming treatment trials [16][17][18] . Recently, first studies showed that such measures of spatio-temporal variability characterizing ataxic gait can also be captured using wearable inertial sensors in clinical assessments 19,20 .…”