PROTACs therapeutically target the polyglutamine androgen receptor inspinal and bulbar muscular atrophy models

Spinal and bulbar muscular atrophy (SBMA) is a CAG/polyglutamine (polyQ) repeat expansion disorder in which the mutant androgen receptor (AR) protein triggers progressive degeneration of the neuromuscular system in men. As the misfolded polyQ AR is the proximal mediator of toxicity, therapeutic efforts have focused on targeting the mutant protein, but these prior efforts have met with limited success in SBMA patients. Here, we examine the efficacy of proteolysis targeting chimeras (PROTACs), small molecule AR degraders that rapidly and potently promote AR ubiquitination and degradation by the proteasome. We identify ARD-1676 as a PROTAC that clears polyQ AR in an over-expression system, in patient iPSC-derived induced motor neurons and skeletal muscle cells, and in a gene targeted mouse model of disease. Furthermore, we demonstrate that 24-hour treatment with ARD-1676 rescues transcriptional dysregulation in SBMA induced skeletal muscle cells. These data provide evidence of therapeutic efficacy and in vivo target engagement, establishing PROTACs as potential therapeutic agents for the treatment of SBMA.