Moving Towards Therapy in SCA1: Insights from Molecular Mechanisms, Identification of Novel Targets, and Planning for Human Trials

Neurotherapeutics. 2019 Oct;16(4):999-1008. doi: 10.1007/s13311-019-00763-y.


The spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders inherited in an autosomal dominant fashion. The SCAs result in progressive gait imbalance, incoordination of the limbs, speech changes, and oculomotor dysfunction, among other symptoms. Over the past few decades, significant strides have been made in understanding the pathogenic mechanisms underlying these diseases. Although multiple efforts using a combination of genetics and pharmacology with small molecules have been made towards developing new therapeutics, no FDA approved treatment currently exists. In this review, we focus on SCA1, a common SCA subtype, in which some of the greatest advances have been made in understanding disease biology, and consequently potential therapeutic targets. Understanding of the underlying basic biology and targets of therapy in SCA1 is likely to give insight into treatment strategies in other SCAs. The diversity of the biology in the SCAs, and insight from SCA1 suggests, however, that both shared treatment strategies and specific approaches tailored to treat distinct genetic causes of SCA are likely needed for this group of devastating neurological disorders.

Keywords: SCA1; Spinocerebellar ataxia; antisense oligonucleotides; biomarkers; clinical trials.; potassium channels.

Publication types

  • Review

MeSH terms

  • Animals
  • Ataxin-1 / antagonists & inhibitors
  • Ataxin-1 / genetics*
  • Ataxin-1 / metabolism
  • Clinical Trials as Topic / methods*
  • Drug Delivery Systems / methods
  • Drug Delivery Systems / trends*
  • Excitatory Amino Acid Agents / administration & dosage
  • Excitatory Amino Acid Agents / metabolism
  • Gene Targeting / methods
  • Gene Targeting / trends*
  • Genetic Therapy / methods
  • Genetic Therapy / trends
  • Humans
  • Oligonucleotides, Antisense / administration & dosage
  • Oligonucleotides, Antisense / genetics
  • Oligonucleotides, Antisense / metabolism
  • RNA Interference / drug effects
  • RNA Interference / physiology
  • Spinocerebellar Ataxias / genetics*
  • Spinocerebellar Ataxias / metabolism
  • Spinocerebellar Ataxias / therapy*


  • ATXN1 protein, human
  • Ataxin-1
  • Excitatory Amino Acid Agents
  • Oligonucleotides, Antisense