Peripheral Androgen Receptor Gene Suppression Rescues Disease in Mouse Models of Spinal and Bulbar Muscular Atrophy

• DOI: 10.1016/j.celrep.2014.02.008
• Publication Date: 2014-04-16T16:00:21Z
• Authors: 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
• Keywords: Muscle Atrophy; clone (Java method)

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