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 2

AR113Q males exhibit no significant spinal cord or NMJ pathology at 26 weeks.

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AR113Q males exhibit no significant spinal cord or NMJ pathology at 26 w...
(A) Immunohistochemistry of spinal cord lumbar enlargement. NeuN is shown in red, MBP in green. White line designates area of neuron quantification. Scale bar: 250 μm. (B) Large neurons in anterior spinal cord lumbar enlargement. NeuN is shown in red, DAPI in blue. Scale bar: 25 μm. (C) Density of large neurons in anterior spinal cord lumbar enlargement (WT, n = 6; AR113Q, n = 5). Data are mean ± SEM. ns, not significant by unpaired Student’s t test; F = 3.372, df = 5. (D) NMJs in TA muscle were visualized by immunofluorescence staining for α-bungarotoxin (red) and neurofilament plus synaptophysin (green). Representative images of NMJs exhibiting full innervation (colocalization ≥50%) and partial innervation (colocalization >20% to <50%). Scale bar: 10 μm. (E and F) NMJ innervation quantified as a box plot (E) or stacked bar graph (F). n = 3 mice per genotype, 100 NMJs per mouse. In E, the box is the interquartile range, the center line is the median, and the whiskers are the minimum and maximum values. NS, not significant by unpaired Student’s t test; F = 1.394, df = 299.