Rescue of spinal cord pathology by peripherally administered AR-targeted ASO in symptomatic AR113Q mice
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PROVIDER: PRJNA1103808 | ENA |
REPOSITORIES: ENA
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Project description: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.
2025-07-31 | GSE264689 | GEO
Project description: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.
2025-08-04 | GSE300077 | GEO
Project description:Rescue of spinal cord pathology by peripherally administered AR-targeted ASO in symptomatic AR113Q mice
| PRJNA1278787 | ENA
Project description:The pattern of gene expression changes was analyzed in the skeletal muscle of transgenic mouse models of Spinal and bulbar muscular atrophy (SBMA) at 1 and 2 month of age.
2023-01-19 | GSE221480 | GEO
Project description:Targeted Antisense Oligonucleotide Treatment Rescues Developmental Alterations in Spinal Muscular Atrophy Organoids [scRNA-seq]
| PRJNA1231114 | ENA
Project description:Purpose: The goal of this study is to evaluate the rescue of SBMA phenotype upon modulation of AR co-factors expression Results: NGS analysis of the transcriptome of quadriceps isolated from SBMA mice upon treatment reveal the rescue (partial or total) of assemblies of genes involved in SBMA pathogenesis Conclusion: targeting overexpressed AR co-regulators is a new therapeutic approach for SBMA to attenuate the toxic GOF without exacerbating AR LOF
2022-11-04 | GSE193539 | GEO
Project description:Emerging evidence implicates transcriptional dyseregulation within skeletal muscle in the pathogenesis of Kennedy disease/spinal bulbar muscular atrophy (KD/SBMA). We therefore broadly characterized gene expression in skeletal muscle of three independently generated mouse models of this disorder. The mouse models included a polyglutamine expanded (polyQ) AR knock-in model (AR113Q KI), a polyQ AR transgenic model (AR97Q Tg), and a transgenic mouse which overexpresses wild type AR solely in muscle (HSA-AR Tg). We performed microarray analysis of lower hindlimb muscles taken from these three models using high density oligonucleotide arrays. Changes in gene expression relative to wild type controls were evaluated separately in each strain. We validated our results using quantitative RT-PCR. Patterns of gene expression that are common to all lines and unique to each are described. When considered globally, the degree of overlap between the three models is approximately equivalent, and several patterns of gene expression relevant to the disease process were observed. Notably, patterns of gene expression typical of loss of AR function were observed in all three models, as were alterations in genes involved in cell adhesion, energy balance, Huntingtonâ??s disease, muscle atrophy and myogenesis. By comparing patterns of gene expression in three independent models of KD/SBMA, we have been able to identify candidate genes that might mediate the core myogenic features of KD/SBMA. Keywords: Gene expression in transgenic mice and disease state analysis We used microarray (38.5K oligo mouse array, which contain 35,302 of 70mer oligonucleotide probes largely derived from constitutively expressed exons and 3,482 of controls) to analyze gene expression in limb muscles of transgenic mice. Three mouse models of KD/SBMA were used: HSA-AR, AR113Q knock-in and AR97Q. HSA-AR transgenic male mice (n=5) and their WT brothers (n=8, all mice were 110-130 days of age) were used in this experiment. ARQ113-Knock In males (n=3, 3-4 months of age), and transgenic AR97Q males and WT brothers (n= 6 of each) were used in this study. For both HSA-AR and AR113Q samples, the log2 ratio of experimental samples (Cy5) and reference RNA(Cy3) was obtained, and log2 ratios from mutant samples were then subtracted from log2 ratios from WT controls. AR97Q males (Cy5) were simply compared with their WT brothers (Cy3) using a log2 ratio, rather than being first compared with reference RNA.
2010-10-12 | E-GEOD-10190 | biostudies-arrayexpress
Project description:Emerging evidence implicates transcriptional dyseregulation within skeletal muscle in the pathogenesis of Kennedy disease/spinal bulbar muscular atrophy (KD/SBMA). We therefore broadly characterized gene expression in skeletal muscle of three independently generated mouse models of this disorder. The mouse models included a polyglutamine expanded (polyQ) AR knock-in model (AR113Q KI), a polyQ AR transgenic model (AR97Q Tg), and a transgenic mouse which overexpresses wild type AR solely in muscle (HSA-AR Tg). We performed microarray analysis of lower hindlimb muscles taken from these three models using high density oligonucleotide arrays. Changes in gene expression relative to wild type controls were evaluated separately in each strain. We validated our results using quantitative RT-PCR. Patterns of gene expression that are common to all lines and unique to each are described. When considered globally, the degree of overlap between the three models is approximately equivalent, and several patterns of gene expression relevant to the disease process were observed. Notably, patterns of gene expression typical of loss of AR function were observed in all three models, as were alterations in genes involved in cell adhesion, energy balance, Huntington’s disease, muscle atrophy and myogenesis. By comparing patterns of gene expression in three independent models of KD/SBMA, we have been able to identify candidate genes that might mediate the core myogenic features of KD/SBMA. Keywords: Gene expression in transgenic mice and disease state analysis
2010-10-12 | GSE10190 | GEO