Current status of treatment of spinal and bulbar muscular atrophy

Abstract

Spinal and bulbar muscular atrophy (SBMA) is the first member identified among polyglutamine diseases characterized by slowly progressive muscle weakness and atrophy of the bulbar, facial, and limb muscles pathologically associated with motor neuron loss in the spinal cord and brainstem. Androgen receptor (AR), a disease-causing protein of SBMA, is a well-characterized ligand-activated transcription factor, and androgen binding induces nuclear translocation, conformational change and recruitment of coregulators for transactivation of AR target genes. Some therapeutic strategies for SBMA are based on these native functions of AR. Since ligand-induced nuclear translocation of mutant AR has been shown to be a critical step in motor neuron degeneration in SBMA, androgen deprivation therapies using leuprorelin and dutasteride have been developed and translated into clinical trials. Although the results of these trials are inconclusive, renewed clinical trials with more sophisticated design might prove the effectiveness of hormonal intervention in the near future. Furthermore, based on the normal function of AR, therapies targeted for conformational changes of AR including amino-terminal (N) and carboxy-terminal (C) (N/C) interaction and transcriptional coregulators might be promising. Other treatments targeted for mitochondrial function, ubiquitin-proteasome system (UPS), and autophagy could be applicable for all types of polyglutamine diseases.

Figure 1

Potential disease-modifying therapies for spinal and bulbar muscular atrophy (SBMA). Ligand-induced nuclear translocation of mutant androgen receptor (AR) is a critical step of motor neuron degeneration in SBMA. In order to block this step, androgen deprivation therapies using leuprorelin and dutasteride have been developed. AR phosphorylation is another potential treatment strategy through attenuation of ligand binding. Insulin-like growth factor-1 (IGF-1) reduces mutant AR toxicity through phosphorylation of AR at the Akt consensus sites. Amino-terminal (N) and carboxy-terminal (C) (N/C) interaction of mutant AR is critical for toxicity, and this interaction is blocked by selective AR modulators such as RTI-016 and RTI-051b. The SBMA modifier melatonin blocks toxic fibrillar and induces nontoxic annular aggregates. As a transcription factor, the binding of AR to DNA in the nucleus is followed by the recruitment of a variety of transcriptional coregulators. 5-Hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one (ASC-J9) disrupts the interaction between AR and its coregulators and yields a therapeutic effect. In SBMA, histone acetylation is impaired, resulting in transcriptional dysregulation. Sodium butyrate, histone deacetylase (HDAC) inhibitor is effective at this step. Furthermore, transcriptionally attenuated genes such as vascular endothelial growth factor (VEGF), dynactin-1, and transforming growth factor β receptor type II (TGF-βRII) are also possible therapeutic targets. Decreased expression of peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1) is one of the causes of mitochondrial dysfunction, and treatments with the antioxidants coenzyme Q10 and idebenone have been developed targeting mitochondria. Mutant AR is degraded through induction of the ubiquitin-proteasome system (UPS) by acyclic isoprenoid geranylgeranylacetone (GGA) and heat shock protein 90 (Hsp90) inhibitors such as 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG). Autophagy induction using rapamycin and trehalose is also effective for AR degradation in fly and cell models of SBMA. However, the opposite results concerning autophagy augmentation therapy were recently reported in SBMA knock-in mice.