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<p>Amyotrophic lateral sclerosis (ALS) involves motor neuron death due to mislocalized TDP-43. Pathologic TDP-43 associates with stress granules (SGs), and lowering the SG-associated protein ataxin-2 (ATXN2) using <i>Atxn2</i>-targeting antisense oligonucleotides prolongs survival in TAR4/4 sporadic ALS mice but failed in clinical trials likely due to poor target engagement. Here we show that an AAV with potent motor neuron transduction delivering <i>Atxn2</i>-targeting miRNAs reduces <i>Atxn2</i> throughout the central nervous system at doses 40x lower than published work. In TAR4/4 mice, miAtxn2 increased survival (50%) and strength, and reduced motor neuron death, inflammation, and phosphorylated TDP-43. TAR4/4 transcriptomic dysregulation recapitulated ALS gene signatures that were rescued by miAtxn2, identifying potential therapeutic mechanisms and biomarkers. In slow progressing hemizygous mice, miAtxn2 slowed disease progression, and in ALS patient-derived lower motor neurons, our AAV vector transduced &gt;95% of cells and potently reduced <i>ATXN2</i> at MOI 4 logs lower than previously reported. These data support AAV-RNAi targeting <i>ATXN2</i> as a translatable therapy for sporadic ALS.</p>

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AAV-based delivery of RNAi targeting ataxin-2 improves survival and pathology in TDP-43 mice

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月25日

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  • Defne A. Amado,
  • Ashley B. Robbins,
  • Katherine R. Whiteman,
  • Alicia R. Smith,
  • Guillem Chillon,
  • Yonghong Chen,
  • Joshua A. Fuller,
  • Nicholas A. Patty,
  • Aleksandar Izda,
  • Congsheng Cheng,
  • Shareen Nelson,
  • Abigail I. Dichter,
  • Esteban O. Mazzoni,
  • Alex Mas Monteys,
  • Beverly L. Davidson

摘要

Amyotrophic lateral sclerosis (ALS) involves motor neuron death due to mislocalized TDP-43. Pathologic TDP-43 associates with stress granules (SGs), and lowering the SG-associated protein ataxin-2 (ATXN2) using Atxn2-targeting antisense oligonucleotides prolongs survival in TAR4/4 sporadic ALS mice but failed in clinical trials likely due to poor target engagement. Here we show that an AAV with potent motor neuron transduction delivering Atxn2-targeting miRNAs reduces Atxn2 throughout the central nervous system at doses 40x lower than published work. In TAR4/4 mice, miAtxn2 increased survival (50%) and strength, and reduced motor neuron death, inflammation, and phosphorylated TDP-43. TAR4/4 transcriptomic dysregulation recapitulated ALS gene signatures that were rescued by miAtxn2, identifying potential therapeutic mechanisms and biomarkers. In slow progressing hemizygous mice, miAtxn2 slowed disease progression, and in ALS patient-derived lower motor neurons, our AAV vector transduced >95% of cells and potently reduced ATXN2 at MOI 4 logs lower than previously reported. These data support AAV-RNAi targeting ATXN2 as a translatable therapy for sporadic ALS.