Gene therapy with AR isoform 2 rescues spinal and bulbar muscular atrophy phenotype by modulating AR transcriptional activity
UMass Chan AffiliationsRNA Therapeutics Institute
Keywordsspinal and bulbar muscular atrophy
androgen receptor protein
Amino Acids, Peptides, and Proteins
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Genetics and Genomics
Nervous System Diseases
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AbstractSpinal 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.
Lim WF, Forouhan M, Roberts TC, Dabney J, Ellerington R, Speciale AA, Manzano R, Lieto M, Sangha G, Banerjee S, Conceição M, Cravo L, Biscans A, Roux L, Pourshafie N, Grunseich C, Duguez S, Khvorova A, Pennuto M, Cortes CJ, La Spada AR, Fischbeck KH, Wood MJA, Rinaldi C. 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. PMID: 34417184; PMCID: PMC8378820. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/42111
Full author list omitted for brevity. For the full list of authors, see article.