Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy (SBMA).

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is an adult-onset, X-linked motor neuron disease characterized by muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. SBMA is caused by the expansion of a CAG triplet repeat, encoding a polyglutamine tract within the first exon of the androgen receptor (AR) gene. The histopathological finding in SBMA is the loss of lower motor neurons in the anterior horn of the spinal cord as well as in the brainstem motor nuclei. There is no established disease-modifying therapy for SBMA. Animal studies have revealed that the pathogenesis of SBMA depends on the level of serum testosterone, and that androgen deprivation mitigates neurodegeneration through inhibition of nuclear accumulation and/or stabilization of the pathogenic AR. Heat shock proteins, the ubiquitin-proteasome system and transcriptional regulation are also potential targets for development of therapy for SBMA. Among these therapeutic approaches, the luteinizing hormone-releasing hormone analogue, leuprorelin, prevents nuclear translocation of aberrant AR proteins, resulting in a significant improvement of disease phenotype in a mouse model of SBMA. In a phase 2 clinical trial of leuprorelin, the patients treated with this drug exhibited decreased mutant AR accumulation in scrotal skin biopsy. Phase 3 clinical trial showed the possibility that leuprorelin treatment is associated with improved swallowing function particularly in patients with a disease duration less than 10 years. These observations suggest that pharmacological inhibition of the toxic accumulation of mutant AR is a potential therapy for SBMA.