Developing treatment for spinal and bulbar muscular atrophy

Abstract

Spinal and bulbar muscular atrophy is unique among the polyglutamine diseases in that the toxicity of the mutant protein, the androgen receptor, is ligand-dependent. In cell culture and animal models the mutant androgen receptor causes protein aggregation and alterations in transcriptional regulation, axonal transport, and mitochondrial function. Various therapeutic approaches have shown efficacy in mouse models, including androgen reduction and agents that alter the processing and degradation of the mutant androgen receptor protein, such as HSP90 inhibitors, IGF-1, and ASC-J9. Clinical trials of androgen-reducing agents have shown indications of efficacy but not proof of clinically meaningful benefit to date. This trial experience has set the stage for future clinical studies of other agents that have been found to be beneficial in transgenic animal models.

Figure 1

Effects of dutasteride on SBMA in a 24 month trial. The change in QMA is not significantly different from placebo, although there was a significant difference in physical quality of life (Fernández-Rhodes et al, 2011).

Figure 2

Improved survival of SBMA mice overexpressing IGF-1, which blocks the ligand-dependant toxicity of the mutant androgen receptor (AR) through phosphatidylinositol-3-kinase (PI3K) and Akt (Palazzolo et al, 2009).