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

DOI: 10.1126/sciadv.abi6896. SCIENCE ADVANCES. 20 Aug 2021. Vol 7, Issue 34

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.

Impact factor: