Peripheral Androgen Receptor Gene Suppression Rescues Disease in Mouse Models of Spinal and Bulbar Muscular Atrophy
Andrew P. Lieberman,
Zhigang Yu,
Sue Murray,
Raechel Peralta,
Audrey Low,
Shuling Guo,
Xing Xian Yu,
Constanza J. Cortes,
C. Frank Bennett,
Brett P. Monia,
Albert R. La Spada,
Gene Hung
Affiliations
Andrew P. Lieberman
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48104, USA
Zhigang Yu
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48104, USA
Sue Murray
Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
Raechel Peralta
Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
Audrey Low
Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
Shuling Guo
Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
Xing Xian Yu
Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
Constanza J. Cortes
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
C. Frank Bennett
Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
Brett P. Monia
Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
Albert R. La Spada
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
Gene Hung
Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
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.
