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

Wooi F. Lim, Mitra Forouhan, Thomas C Roberts, Jesse Dabney, Ruth Ellerington, Alfina A Speciale, Raquel Manzano, Maria Lieto, Gavinda Sangha, Subhashis Banerjee, Mariana Conceicao, Lara Cravo, Anabelle Biscans, Loic Roux, Naemeh Pourshafle, Christopher Grunseich, Stephanie Duguez, Anastasia Khvorova, Maria Pennuto, Constanza J CortesAlbert R La Spada, Kenneth H Fischbeck, Matthew JA Wood, Carlo Rinaldi

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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.
Original languageEnglish
Article numberabi6896
Number of pages15
JournalScience Advances
Volume7
Issue number34
Early online date20 Aug 2021
DOIs
Publication statusE-pub ahead of print - 20 Aug 2021

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