Spinocerebellar ataxias caused by polyglutamine expansions: a review of therapeutic strategies.

Abstract:

Six of the spinocerebellar ataxias (SCAs) are caused by expanded CAG trinucleotide repeats encoding polyglutamine tracts in different genes. Together with three other neurodegenerative diseases they represent the polyglutamine repeat disorders. These disorders share many pathological features beyond a common genetic mechanism. They are the subject of considerable research efforts to elucidate their basic pathophysiologies, with the hope of using this knowledge to develop disease modifying treatments. Here we examine the biology that underpins possible therapeutic strategies for the SCAs caused by CAG repeats and review supportive data from cell and animal models. Therapeutic strategies include silencing gene expression, increasing protein clearance, reducing the toxicity of the protein, influencing downstream pathways activated by the mutant protein and transplantation. We also consider strategies which have been tested in other polyglutamine diseases that may generalize to these SCAs. Finally, we review clinical trials and consider the problems of translating the increasing amount of promising laboratory data into human trials.