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

Lim, Wooi F ; Forouhan, Mitra ; Roberts, Thomas C ; Dabney, Jesse ; Ellerington, Ruth ; Speciale, Alfina A ; Manzano, Raquel (Universidad de Zaragoza) ; Lieto, Maria ; Sangha, Gavinda ; Banerjee, Subhashis ; Conceição, Mariana ; Cravo, Lara ; Biscans, Annabelle ; Roux, Loïc ; Pourshafie, Naemeh ; Grunseich, Christopher ; Duguez, Stephanie ; Khvorova, Anastasia ; Pennuto, Maria ; Cortes, Constanza J ; La Spada, Albert R ; Fischbeck, Kenneth H ; Wood, Matthew JA ; Rinaldi, Carlo

Resumen: 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 regu-latory switch of AR genomic functions in androgen-responsive tissues. Delivery of this isoform using a recombi-nant adeno-associated virus vector type 9 resulted in amelioration of the disease phenotype in SBMA mice by restoring polyQ AR–dysregulated transcriptional activity

Idioma: Inglés

DOI: 10.1126/sciadv.abi6896

Año: 2021

Publicado en: Science advances 7, 34 (2021), eabi6896 [15 pp.]
ISSN: 2375-2548

Factor impacto JCR: 14.98 (2021)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 7 / 74 = 0.095 (2021) - Q1 - T1

Tipo y forma: Article (Published version)

Área (Departamento): Área Genética (Dpto. Anatom.,Embri.Genét.Ani.)