Rescue of spinal cord pathology by peripherally administered AR-targeted ASO in symptomatic AR113Q mice
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ABSTRACT:
PROVIDER: PRJNA1278787 | 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.
2025-08-04 | GSE300077 | 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.
2025-07-31 | GSE264689 | GEO
Project description:Peripherally administered androgen receptor-targeted antisense oligonucleotide rescues spinal pathology in a murine SBMA model
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Project description:The objective of this study is to evaluate ASO biodistribution and pharmacodynamic response following intravenous delivery of conjugated OTV, which utilizes transferrin-receptor binding to deliver ASO, vs. intrathecal delivery of naked ASO in cynomolgus monkeys, the current gold standard for ASO delivery. Three groups were included for comparison: 1) Negative control cohort = Four biweekly intravenous doses of saline (n=3); 2) IT cohort = Single intrathecal dose of 4mg MALAT1 ASO (n=3); 3) OTV multi dose cohort = Four biweekly intravenous doses of 30mpk OTV:MALAT1 (n=3). Tissues were collected two weeks after the final dose to allow sufficient time for target knockdown. Brain, spinal cord, and peripheral tissues were dissected and frozen for molecular analysis. Compared to an intrathecal injection of ASO, systemic administration of OTV resulted in significantly more homogenous biodistribution of ASO in the central nervous system as measured by a probe-based hybridization assay as well as staining with an anti-ASO antibody. One potential consequence of heterogeneous ASO distribution is heterogeneous target knockdown throughout the CNS. We observed more consistent target knockdown throughout the cortex, subcortical areas, and spinal cord of monkeys dosed peripherally with OTV. By contrast, monkeys dosed intrathecally with naked ASO showed much more knockdown in the spinal cord compared to the brian, consistent with ASO distribution.
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Project description:To gain more insights into the functional significance of lnc-HLX-2-7, gene expression profiles were measured using D425 (sh-CTRL), D425 (sh-HLX) and intracranial D425 xenografts treated with ASO-CTRL and ASO-lnc-HLX 2-7 by RNA sequencing.
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Project description:Transcriptional profiling of mouse liver comparing control, scrambled-oligonucleotides (Cont)-treated mice with Perilipin 2-antisense oligonucleotides (Plin2-ASO)-treated mice. C57BL/6 mice on a high-fat diet were treated with oligonucleotides in vivo. The goal was to determine the effects of Plin2 down-regulation in the liver on global gene expression. Two-condition experiment, control oligonucleotides vs. Plin2-antisense oligonucleotides. Biological replicates: 4 control replicates, 4 Plin2-ASO replicates.
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Project description:RNA-targeting approaches have improved disease symptoms in preclinical rodent models of several neurological diseases. Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited ataxia caused by expansion of a polyglutamine tract in the encoded protein Ataxin-1 (ATXN1). Despite advances in understanding this CAG repeat/polyglutamine expansion disease, there are still no therapies to alter its progressive fatal course. Here we investigate the therapeutic capability of an antisense oligonucleotide (ASO) targeting mouse Atxn1 in Atxn 1 154Q/2Q knockin mice that manifest motor deficits and premature lethality. Following a single ASO treatment at 5 weeks of age, mice demonstrated rescue of these disease-associated phenotypes. In addition, RNA-seq on vehicle-treated Atxn1 154Q/2Q and ASO-treated Atxn1 154Q/2Q mice were used to demonstrate molecular differences between SCA1 pathogenesis in the cerebellum that underlies ataxia with disease in the medulla associated with lethality. Together, these findings support the efficacy and therapeutic importance of directly targeting ATXN1 expression as a strategy to rescue both motor deficits and lethality seen in SCA1.
2019-05-31 | GSE114674 | GEO
Project description:Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia. Currently, no preventative or disease-modifying treatments exist for this progressive neurodegenerative disorder, although efforts using gene silencing approaches are under clinical trial investigation. The disease is caused by a CAG repeat expansion in the mutant gene, ATXN3, producing an enlarged polyglutamine tract in the mutant protein. Similar to other paradigmatic neurodegenerative diseases, studies evaluating the pathogenic mechanism focus primarily on neuronal implications. Consequently, therapeutic interventions often overlook non-neuronal contributions to disease. Our lab recently reported that oligodendrocytes display some of the earliest and most progressive dysfunction in SCA3 mice. Evidence of disease-associated oligodendrocyte signatures has also been reported in other neurodegenerative diseases, including Alzheimer's disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, and Huntington's disease. Here, we assess the effects of anti-ATXN3 antisense oligonucleotide (ASO) treatment on oligodendrocyte dysfunction in premanifest and symptomatic SCA3 mice. We report a severe, but modifiable, deficit in oligodendrocyte maturation caused by the toxic gain-of-function of mutant ATXN3 early in SCA3 disease that is transcriptionally, biochemically, and functionally rescued with anti-ATXN3 ASO. Our results highlight the promising use of an ASO therapy across neurodegenerative diseases that requires glial targeting in addition to affected neuronal populations.
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