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Cell Rep. 2014 May 8;7(3):774-84. doi: 10.1016/j.celrep.2014.02.008. Epub 2014 Apr 16.

Peripheral androgen receptor gene suppression rescues disease in mouse models of spinal and bulbar muscular atrophy.

Author information

1
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48104, USA. Electronic address: liebermn@umich.edu.
2
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48104, USA.
3
Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
4
Departments of Cellular and Molecular Medicine, Neuroscience, and Pediatrics, Institute for Genomic Medicine, and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
5
Departments of Cellular and Molecular Medicine, Neuroscience, and Pediatrics, Institute for Genomic Medicine, and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Division of Genetics/Dysmorphology, Rady Children's Hospital, San Diego, CA 92037, USA.
6
Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA. Electronic address: ghung@isisph.com.

Abstract

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.

Comment in

PMID:
24746732
PMCID:
PMC4356525
DOI:
10.1016/j.celrep.2014.02.008
[Indexed for MEDLINE]
Free PMC Article

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