Targeting overexpressed transcription co-regulators to suppress SBMA

Kennedy’s disease is caused by a mutation in the androgen receptor (AR). AR is the receptor of testosterone, the male hormone, and of note, only males show symptoms of the disease. AR is a transcription factor, which means that it controls what the cells need to produce (express) or not to stay healthy. It does so by interacting with other proteins called transcriptional coactivators. The mutation leads to a protein with altered functions; some are lost, and others are enhanced. We have collected evidence that by modulating the interaction with two specific AR partners that are increased during the disease in skeletal muscle, we can reduce the aberrant AR activity while preserving its normal function. We propose to explore novel and more specific strategies to move our approach to the clinics using either adeno-associated viruses or nanoparticles driven to muscle to inhibit these two factors and test whether this could be a successful therapeutic strategy for patients. Our experimental approach is based on strong preliminary data and is relevant because it may allow us to move our tools to phase I clinical trial.