Gene therapy with AR isoform 2 rescues spinal and bulbar muscular atrophy phenotype by modulating AR transcriptional activity
Wooi Fang Lim, Mitra Forouhan, Thomas C. Roberts, Jesse Dabney, Ruth Ellerington, Alfina A. Speciale, Raquel Manzano, Maria Lieto, Gina Sangha, Subhashis Banerjee, Mariana Conceição, Lara Cravo, Annabelle Biscans, Loïc Roux, Naemeh Pourshafie, Christopher Grunseich, Stéphanie Duguez, Anastasia Khvorova, Maria Pennuto, Constanza J. Cortés, Albert R. La Spada, Kenneth H. Fischbeck, Matthew J. A. Wood, Carlo Rinaldi
Abstract
Spinal and bulbar muscular atrophy (SBMA) is an X-linked, adult-onset neuromuscular condition caused by an abnormal polyglutamine (polyQ) tract expansion in androgen receptor (AR) protein. SBMA is a disease with high unmet clinical need. Recent studies have shown that mutant AR-altered transcriptional activity is key to disease pathogenesis. Restoring the transcriptional dysregulation without affecting other AR critical functions holds great promise for the treatment of SBMA and other AR-related conditions; however, how this targeted approach can be achieved and translated into a clinical application remains to be understood. Here, we characterized the role of AR isoform 2, a naturally occurring variant encoding a truncated AR lacking the polyQ-harboring domain, as a regulatory switch of AR genomic functions in androgen-responsive tissues. Delivery of this isoform using a recombinant adeno-associated virus vector type 9 resulted in amelioration of the disease phenotype in SBMA mice by restoring polyQ AR-dysregulated transcriptional activity.