Cell Reports
Volume 7, Issue 3, 8 May 2014, Pages 774-784
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Article
Peripheral Androgen Receptor Gene Suppression Rescues Disease in Mouse Models of Spinal and Bulbar Muscular Atrophy

https://doi.org/10.1016/j.celrep.2014.02.008Get rights and content
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Highlights

  • AR-targeted antisense oligonucleotides suppressed gene expression in mice

  • Subcutaneous delivery suppressed AR gene expression in the periphery but not the CNS

  • Subcutaneous administration rescued disease in two mouse models of SBMA

  • Peripherally expressed polyQ AR contributes to disease and is a therapeutic target

Summary

Spinal and bulbar muscular atrophy (SBMA) is caused by the polyglutamine androgen receptor (polyQ-AR), a protein expressed by both lower motor neurons and skeletal muscle. Although viewed as a motor neuronopathy, data from patients and mouse models suggest that muscle contributes to disease pathogenesis. Here, we tested this hypothesis using AR113Q knockin and human bacterial artificial chromosome/clone (BAC) transgenic mice that express the full-length polyQ-AR and display androgen-dependent weakness, muscle atrophy, and early death. We developed antisense oligonucleotides that suppressed AR gene expression in the periphery but not the CNS after subcutaneous administration. Suppression of polyQ-AR in the periphery rescued deficits in muscle weight, fiber size, and grip strength, reversed changes in muscle gene expression, and extended the lifespan of mutant males. We conclude that polyQ-AR expression in the periphery is an important contributor to pathology in SBMA mice and that peripheral administration of therapeutics should be explored for SBMA patients.

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This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).