Gene therapy with AR isoform 2 rescues spinal and bulbar muscular atrophy phenotype by modulating AR transcriptional activity

Journal article

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.

Authors: Lim, WF; Forouhan, M; Roberts, TC; Dabney, J; Ellerington, R

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Association for the Advancement of Science
• Journal: Science Advances
• Volume: 7
• Issue: 34
• Article number: eabi6896
• Publication date: 2021-08-20
• Acceptance date: 2021-06-30
• DOI: 10.1126/sciadv.abi6896
• EISSN: 2375-2548
• Pmid: 34417184
• Language: English
• Keywords: FFR