Peripherally administered androgen receptor–targeted antisense oligonucleotide rescues spinal pathology in a murine SBMA model
Changwoo Lee, Zhigang Yu, Curtis J. Kuo, Leon Tejwani, Rosalie M. Grijalva, Eunwoo Bae, Hien T. Zhao, Janghoo Lim, Andrew P. Lieberman
Changwoo Lee, Zhigang Yu, Curtis J. Kuo, Leon Tejwani, Rosalie M. Grijalva, Eunwoo Bae, Hien T. Zhao, Janghoo Lim, Andrew P. Lieberman
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Research Article Neuroscience

Peripherally administered androgen receptor–targeted antisense oligonucleotide rescues spinal pathology in a murine SBMA model

Abstract

Degeneration of the neuromuscular system is a characteristic feature of spinal and bulbar muscular atrophy (SBMA), a CAG/polyglutamine (polyQ) expansion disorder caused by mutation in the androgen receptor (AR). Using a gene-targeted mouse model of SBMA, AR113Q mice, we demonstrate age-dependent degeneration of the neuromuscular system that initially manifests with muscle weakness and atrophy and progresses to include denervation of neuromuscular junctions and lower motor neuron soma atrophy. Using this model, we tested the hypothesis that therapeutic intervention targeting skeletal muscle during this period of disease progression arrests degeneration of the neuromuscular system. To accomplish this, AR-targeted antisense oligonucleotides were administered subcutaneously to symptomatic AR113Q mice to reduce expression of polyQ AR in peripheral tissues but not in the spinal cord. This intervention rescued muscle atrophy, neuromuscular junction innervation, lower motor neuron soma size, and survival in aged AR113Q mice. Single-nucleus RNA sequencing revealed age-dependent transcriptional changes in the AR113Q spinal cord during disease progression, which were mitigated by peripheral AR gene silencing. Our findings underscore the intricate interplay between peripheral tissues and the central nervous system in SBMA and emphasize the therapeutic effectiveness of peripheral gene knockdown in symptomatic disease.

Authors

Changwoo Lee, Zhigang Yu, Curtis J. Kuo, Leon Tejwani, Rosalie M. Grijalva, Eunwoo Bae, Hien T. Zhao, Janghoo Lim, Andrew P. Lieberman

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Figure 3

Peripheral ASO administration from 26 to 52 weeks rescues survival and ameliorates skeletal muscle atrophy.

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Peripheral ASO administration from 26 to 52 weeks rescues survival and a...
AR113Q males at 26 weeks were given ASO (25 mg/kg body weight) or vehicle subcutaneously, once per week until 52 weeks. (A) TA muscle fibers from WT, AR113Q, or AR113Q plus ASO males were visualized by FITC-WGA. Nuclei were stained with DAPI (blue). Scale bar: 50 μm. (B and C) TA fiber size quantified as a histogram of frequency distribution (B) and box plot (C). In C, the box is the interquartile range, the center line is the median, and the whiskers are the minimum and maximum values. n = 3 mice per group, >100 fibers per mouse. ****P < 0.0001 by 1-way ANOVA with Tukey’s multiple-comparison test, F = 424.7, df = 2. (D) Survival curve of WT, AR113Q, and AR113Q plus ASO mice (WT, n = 15; AR113Q, n = 11; AR113Q + ASO, n = 15). NS, not significant; *P < 0.05, **P < 0.01 by log-rank test with Bonferroni’s correction, χ2 = 16.07, df = 2. (E) Grip strength of WT, AR113Q, and AR113Q plus ASO mice at 52 weeks (WT, n = 7; AR113Q, n = 8; AR113Q + ASO, n = 8). Data are mean ± SEM. ***P < 0.001, ****P < 0.0001 by 1-way ANOVA with Tukey’s multiple-comparison test, F = 18.72, df = 2. (F) Body weight of WT, AR113Q, and AR113Q plus ASO mice at 52 weeks (WT, n = 7; AR113Q, n = 8; AR113Q + ASO, n = 8). Data are mean ± SEM. ****P < 0.0001 by 1-way ANOVA with Tukey’s multiple-comparison test, F = 39.40, df = 2.