Towards A Therapeutic Intervention in Polyglutamine Ataxias: From Models to Clinical Trials

The autosomal dominant (AD) forms of hereditary ataxias compose a heterogeneous group of diseases, in which cerebellar degeneration and dysfunction is consistently present. Polyglutamine (polyQ) ataxias are a subset of AD ataxias, comprising spinocerebellar ataxias (SCAs) 1, 2, 3, 6, 7 and 17, as well as dentatorubral-pallydoluysian atrophy (DRPLA), all caused by a CAG expansion in the coding region of the corresponding gene, leading to the formation of a pathological polyglutamine stretch. The pathogenic process underlying these disorders has been extensively investigated, but it remains incompletely understood; as a consequence, therapeutic targets have been difficult to identify. Models of polyQ SCAs have proven to be of great utility for the understanding of the underlying pathogenic processes; in particular, animal models mimicking the evolution of these diseases are considered to be of great utility in the evaluation of the efficacy of diseasemodifying compounds, before they can be translated into patient trials. In this chapter, we review the common mechanisms in polyQ ataxias pathogenesis and summarize the evidence provided by cell and animal models of SCAs concerning the potential benefits of several compounds which have been studied in a preclinical setup. A collection of the published data on clinical trials conducted so far in polyQ SCAs is presented and the main limitations currently imposed to trials in this group of disorders are discussed.

Keywords: Animal models, CAG expansion, cell models, clinical trials, DRPLA, late onset disease, neurodegenerative disorder, rare disease, SCA1, SCA17, SCA2, SCA3, SCA6, SCA7, spinocerebellar ataxia, therapy, treatment.