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

Sci Adv. 2021 Aug 20;7(34):eabi6896. doi: 10.1126/sciadv.abi6896. Print 2021 Aug.


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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bulbo-Spinal Atrophy, X-Linked* / genetics
  • Bulbo-Spinal Atrophy, X-Linked* / therapy
  • Genetic Therapy
  • Mice
  • Phenotype
  • Protein Isoforms / genetics
  • Receptors, Androgen* / genetics
  • Receptors, Androgen* / metabolism


  • Protein Isoforms
  • Receptors, Androgen