doi:10.1126/sciadv.abi6896engLim, Wooi FForouhan, MitraRoberts, Thomas CDabney, JesseEllerington, RuthSpeciale, Alfina AManzano, RaquelLieto, MariaSangha, GavindaBanerjee, SubhashisConceição, MarianaCravo, LaraBiscans, AnnabelleRoux, LoïcPourshafie, NaemehGrunseich, ChristopherDuguez, StephanieKhvorova, AnastasiaPennuto, MariaCortes, Constanza JLa Spada, Albert RFischbeck, Kenneth HWood, Matthew JARinaldi, CarloGene therapy with AR isoform 2 rescues spinal and bulbar muscular atrophy phenotype by modulating AR transcriptional activityART-2021-125124Spinal 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 activity2021http://zaguan.unizar.es/record/10850910.1126/sciadv.abi6896http://zaguan.unizar.es/record/108509oai:zaguan.unizar.es:108509Science advances 7, 34 (2021), eabi6896 [15 pp.]byhttp://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccess