Molecular Mechanisms and Therapeutics for SBMA/Kennedy's Disease.

ABSTRACT

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by a polyglutamine (polyQ) expansion in the androgen receptor (AR). Despite the fact that the monogenic cause of SBMA has been known for nearly 3 decades, there is no effective treatment for this disease, underscoring the complexity of the pathogenic mechanisms that lead to a loss of motor neurons and muscle in SBMA patients. In the current review, we provide an overview of the system-wide clinical features of SBMA, summarize the structure and function of the AR, discuss both gain-of-function and loss-of-function mechanisms of toxicity caused by polyQ-expanded AR, and describe the cell and animal models utilized in the study of SBMA. Additionally, we summarize previously conducted clinical trials which, despite being based on positive results from preclinical studies, proved to be largely ineffective in the treatment of SBMA; nonetheless, these studies provide important insights as researchers develop the next generation of therapies.