||Progress toward the development of treatment of spinal and bulbar muscular atrophy
Sahashi, Kentaro ,
Hashizume, Atsushi ,
Sobue, GenKatsuno, Masahisa
Expert Opinion on Orphan Drugs
514 , 2017-05-25 , Taylor & Francis
Introduction: With greater longevity, the prevalence of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis is increasing, but these diseases remain intractable. This is also the case for a hereditary motor neuron disease, spinal and bulbar muscular atrophy or SBMA. Areas covered: SBMA typically affects adult males, eliciting motor deficits due to progressive loss of lower motor neurons, while females do not manifest neurological signs. It results from a CAG-trinucleotide repeat expansion in the androgen receptor or AR gene which is translated into an expanded polyglutamine tract within the encoded protein. Ligand-dependent nuclear accumulation of the mutant AR is implicated to lead to transcriptional dysregulation and subsequent defects in pivotal cellular functions, causing motor neuron death. Expert opinion: Even though the pathogenesis has not been fully understood, recent advances especially in the dissection of pathomechanisms associated with the pathogenic AR protein and aggregates accelerate the development of potential targeted therapeutics such as administration of leuprorelin acetate, a potent luteinizing hormone-releasing hormone analog, which has been successfully tested in clinical trials. Combination therapies antagonizing causative mutant AR and its downstream targets hold promise to further open a therapeutic avenue for the establishment of disease modifying drugs for SBMA.