Article Abstract

Precision medicine in spinocerebellar ataxias: treatment based on common mechanisms of disease

Authors: David D. Bushart, Geoffrey G. Murphy, Vikram G. Shakkottai

Abstract

Spinocerebellar ataxias (SCAs) are a heterogeneous group of dominantly inherited neurodegenerative disorders affecting the cerebellum and its associated pathways. There are no available symptomatic or disease-modifying therapies available for any of the over 30 known causes of SCA. In order to develop precise treatments for SCAs, two strategies can be employed: (I) the use of gene-targeting strategies to silence disease-causing mutant protein expression, and (II) the identification and targeting of convergent mechanisms of disease across SCAs as a basis for treatment. Gene targeting strategies include RNA interference and antisense oligonucleotides designed to silence mutant genes in order to prevent mutant protein expression. These therapies can be precise, but delivery is difficult and many disease-causing mutations remain unknown. Emerging evidence suggests that several common disease mechanisms may exist across SCAs. Disrupted protein homeostasis, RNA toxicity, abnormal synaptic signaling, altered intracellular calcium handling, and altered Purkinje neuron membrane excitability are all disease mechanisms which are seen in multiple etiologies of SCA and could potentially be targeted for treatment. Clinical trials with drugs such as riluzole, a potassium channel activator, show promise for multiple SCAs and suggest that convergent disease mechanisms do exist and can be targeted. Precise treatment of SCAs may be best achieved through pharmacologic agents targeting specific disrupted pathways.

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