title: Peripheral androgen receptor gene suppression rescues disease in mouse models of spinal and bulbar muscular atrophy.
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.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48104, USA. Electronic address: liebermn@umich.edu.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lieberman
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48104, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
authors.forename: Sue
authors.initials: S
authors.lastname: Murray
authors.affiliation: Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
authors.forename: Raechel
authors.initials: R
authors.lastname: Peralta
authors.affiliation: Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Low
authors.affiliation: Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
authors.forename: Shuling
authors.initials: S
authors.lastname: Guo
authors.affiliation: Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
authors.forename: Xing Xian
authors.initials: XX
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Constanza J
authors.initials: CJ
authors.lastname: Cortes
authors.affiliation: Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.affiliation: Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.affiliation: 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.
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
authors.affiliation: Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA. Electronic address: ghung@isisph.com.
authors.forename: Gene
authors.initials: G
authors.lastname: Hung
mesh_terms: D000818:Animals; D001835:Body Weight; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D018737:Hand Strength / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020966:Muscular Disorders, Atrophic / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D010641:Phenotype; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015996:Survival Rate; D013739:Testosterone / Q000097:blood; D059467:Transcriptome
chemical_list: D016376:Oligonucleotides, Antisense; D011944:Receptors, Androgen; D013739:Testosterone
references.citation: Curr Opin Pharmacol. 2008 Dec;8(6):752-8
references.pmid: 18775514
references.citation: Nucleic Acids Res. 1994 Aug 11;22(15):3181-6
references.pmid: 8065934
references.citation: Neuron. 2002 Aug 29;35(5):855-64
references.pmid: 12372281
references.citation: J Cell Biol. 2009 Dec 14;187(6):761-72
references.pmid: 19951898
references.citation: Neuron. 2004 Mar 4;41(5):687-99
references.pmid: 15003169
references.citation: Exp Neurol. 2006 Jul;200(1):8-18
references.pmid: 16513111
references.citation: Am J Pathol. 2006 Jan;168(1):195-204
references.pmid: 16400023
references.citation: Mol Med. 2012 Dec 06;18:1261-8
references.pmid: 22952056
references.citation: Drug Metab Dispos. 2007 Mar;35(3):460-8
references.pmid: 17172312
references.citation: EMBO Mol Med. 2013 Oct;5(10):1586-601
references.pmid: 24014320
references.citation: J Comp Neurol. 2004 May 17;473(1):59-72
references.pmid: 15067718
references.citation: Nat Genet. 1993 Oct;5(2):184-8
references.pmid: 8252045
references.citation: Hum Mol Genet. 2011 Nov 15;20(22):4475-90
references.pmid: 21873607
references.citation: Expert Opin Drug Metab Toxicol. 2009 Apr;5(4):381-91
references.pmid: 19379126
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18259-64
references.pmid: 17984063
references.citation: PLoS Genet. 2011 Oct;7(10):e1002321
references.pmid: 22022281
references.citation: Neuron. 2002 Aug 29;35(5):843-54
references.pmid: 12372280
references.citation: Nat Neurosci. 2007 May;10(5):608-14
references.pmid: 17435754
references.citation: Neuron. 2009 Aug 13;63(3):316-28
references.pmid: 19679072
references.citation: Muscle Nerve. 2000 Jun;23(6):843-50
references.pmid: 10842259
references.citation: J Biol Chem. 2004 Feb 27;279(9):8389-95
references.pmid: 14670946
references.citation: Neuron. 2012 Jun 21;74(6):1031-44
references.pmid: 22726834
references.citation: J Clin Invest. 2006 Oct;116(10):2663-72
references.pmid: 16981011
references.citation: Dis Model Mech. 2009 Sep-Oct;2(9-10):500-7
references.pmid: 19692580
references.citation: Neuron. 2003 Sep 25;40(1):41-52
references.pmid: 14527432
references.citation: Hum Mol Genet. 2000 Sep 1;9(14):2197-202
references.pmid: 10958659
references.citation: Curr Opin Neurobiol. 2000 Oct;10(5):599-611
references.pmid: 11084323
references.citation: Hum Mol Genet. 2002 Aug 15;11(17):1967-76
references.pmid: 12165558
references.citation: Nature. 2011 Oct 05;478(7367):123-6
references.pmid: 21979052
references.citation: J Med Chem. 2009 Jan 8;52(1):10-3
references.pmid: 19086780
references.citation: Science. 2006 Jun 2;312(5778):1389-92
references.pmid: 16741123
references.citation: Hum Mol Genet. 2009 Jan 1;18(1):27-42
references.pmid: 18824496
references.citation: Am J Hum Genet. 1999 Oct;65(4):966-73
references.pmid: 10486315
references.citation: Hum Mol Genet. 2000 Jan 22;9(2):267-74
references.pmid: 10607837
references.citation: Neurobiol Dis. 2009 Apr;34(1):113-20
references.pmid: 19211034
references.citation: Hum Mol Genet. 2008 Dec 15;17(24):3942-52
references.pmid: 18784277
references.citation: J Neurosci. 2006 Nov 22;26(47):12106-17
references.pmid: 17122035
references.citation: Hum Mol Genet. 1995 Apr;4(4):523-7
references.pmid: 7633399
references.citation: Nature. 2012 Jul 26;487(7408):443-8
references.pmid: 22801498
references.citation: Hum Mol Genet. 2006 Jun 1;15(11):1876-83
references.pmid: 16644868
references.citation: Nat Neurosci. 2013 May;16(5):571-9
references.pmid: 23542689
references.citation: Nature. 2012 Aug 2;488(7409):111-5
references.pmid: 22859208
references.citation: Arch Neurol. 2002 Dec;59(12):1921-6
references.pmid: 12470181
references.citation: J Comp Neurol. 1997 Mar 3;379(1):88-98
references.pmid: 9057114
references.citation: J Biol Chem. 2010 May 21;285(21):15714-23
references.pmid: 20348093
references.citation: Nat Chem Biol. 2013 Feb;9(2):112-8
references.pmid: 23222885
references.citation: Nat Neurosci. 2006 Jul;9(7):907-16
references.pmid: 16751763
references.citation: J Cell Biol. 2001 Mar 5;152(5):1107-14
references.pmid: 11238465
references.citation: Nat Neurosci. 2008 Mar;11(3):251-3
references.pmid: 18246065
references.citation: Nucleic Acids Res. 2011 Jun;39(11):4795-807
references.pmid: 21345934
references.citation: Neuron. 2014 Apr 16;82(2):295-307
references.pmid: 24742458
references.citation: Hum Mol Genet. 2011 Nov 15;20(22):4334-44
references.pmid: 21840928