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

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 and Beverly L. Davidson ()
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Defne A. Amado: University of Pennsylvania
Ashley B. Robbins: Children’s Hospital of Philadelphia
Katherine R. Whiteman: Children’s Hospital of Philadelphia
Alicia R. Smith: Children’s Hospital of Philadelphia
Guillem Chillon: Children’s Hospital of Philadelphia
Yonghong Chen: Children’s Hospital of Philadelphia
Joshua A. Fuller: Children’s Hospital of Philadelphia
Nicholas A. Patty: Children’s Hospital of Philadelphia
Aleksandar Izda: Children’s Hospital of Philadelphia
Congsheng Cheng: Children’s Hospital of Philadelphia
Shareen Nelson: Children’s Hospital of Philadelphia
Abigail I. Dichter: Children’s Hospital of Philadelphia
Esteban O. Mazzoni: NYU Grossman School of Medicine
Alex Mas Monteys: Children’s Hospital of Philadelphia
Beverly L. Davidson: Children’s Hospital of Philadelphia

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-60497-8

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