Targeted Molecular Therapies for SBMA.

Spinal and bulbar muscular atrophy (SBMA) is a late-onset neuromuscular disease caused by a polyglutamine expansion in the androgen receptor gene which results in progressive spinal and bulbar motor neuron degeneration, and muscle atrophy. Although the causative genetic defect is known, until recently, the molecular pathogenesis of the disease was unclear, resulting in few, if any, targets for therapy development. However, over the past decade, our understanding of the pathomechanisms that play a role in SBMA has increased dramatically, and several of these pathways and mechanisms have now been investigated as possible therapeutic targets. In this review, we discuss some of the key pathomechanisms implicated in SBMA and describe some of the therapeutic strategies that have been tested in SBMA to date, which fall into four main categories: (i) gene silencing; (ii) protein quality control and/or increased protein degradation; (iii) androgen deprivation; and (iv) modulation of AR function. Finally, it is also now clear that in addition to a greater understanding of the molecular mechanisms that underlie disease, the development of an effective disease modifying therapy for SBMA will require the coordinated, collaborative effort of research teams with diverse areas of expertise, clinicians, pharmaceutical companies as well as patient groups.