UMMS Affiliation

RNA Therapeutics Institute

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Document Type



Amino Acids, Peptides, and Proteins | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetics and Genomics | Musculoskeletal Diseases | Nervous System Diseases | Therapeutics


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.


spinal and bulbar muscular atrophy, androgen receptor protein

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Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY)

DOI of Published Version



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

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Science advances


Full author list omitted for brevity. For the full list of authors, see article.

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Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.