ArticleMolecular therapy : the journal of the American Society of Gene Therapy2025
Dorsal root ganglion toxicity after AAV intra-CSF delivery of a RNAi expression construct into non-human primates and mice.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed.
- Antisense oligonucleotide treatment following viral delivery of artificial SOD1-targeting miRNA shows improved efficacy in SOD1-G93A mice.Molecular therapy. Advances · 2026Article
- Intravenous administration of an engineered AAV9-gene-silencing vector suppresses human SOD1 and extends survival in an ALS mouse model.Nature communications · 2026Article
- Safety, efficacy, and distal nerve Schwann cell biodistribution in mice and NHPs to support translation of AAV9 RNAi therapy for CMT1A.Molecular therapy. Nucleic acids · 2026Article
- Review
- RNA Therapeutics Targeting Skeletal Muscle: Emerging Antisense and Gene-Modifying Strategies.Biomolecules · 2026Review
- RNAi-Induced Expression of Paternal UBE3A.Genes · 2026Article
- Variability in the circulation of cerebrospinal fluid: causes and clinical implications for intraventricular drug delivery.Frontiers in drug delivery · 2026Review
- Transcriptional changes in non-human primate tissues after intrathecal delivery of serotype 9 adeno-associated viral vector: Insights into organ toxicities.Molecular therapy. Methods & clinical development · 2025Article
- Inhibition of immune response reduces pathology in dorsal root ganglia and peripheral nerves in cynomolgus macaques following AAV gene therapy.Molecular therapy. Methods & clinical development · 2025Article
- An AAV-Based Therapy Approach for Neurological Phenotypes of X-Linked Adrenoleukodystrophy.International journal of molecular sciences · 2025Review
- Insights into the mechanisms of microRNAs in hepatoblastoma: from diagnosis to treatment.Precision clinical medicine · 2025Review
- Treating Hearing Loss: From Cochlear Implantation to Gene Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Programmable self-replicating JEV nanotherapeutics redefine RNA delivery in ALS.Communications biology · 2025Review
- Beyond single targets: leveraging degeneracy in sodium channels for osteoarthritis analgesia.Pain reports · 2025Article
- Viral-mediated knockdown of Atxn2 attenuates TDP-43 pathology and muscle dysfunction in the PFN1Acta neuropathologica communications · 2025Article
- AAV-RNAi constructs promote DRG toxicity.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
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26 authors.
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No grant is acknowledged in the PubMed record.
Abstract
Dorsal root ganglion (DRG) toxicity has been consistently reported as a potential safety concern after delivery of adeno-associated viruses (AAVs) containing gene-replacement vectors but has yet to be reported for RNAi-based vectors. Here, we report DRG toxicity after AAV intra-CSF delivery of an RNAi expression construct-artificial microRNA targeting superoxide dismutase 1 (SOD1)-in non-human primates (NHPs) and provide evidence that this can be recapitulated within mice. Histopathology evaluation showed that NHPs and mice develop DRG toxicity after AAV delivery, including DRG neuron degeneration and necrosis and nerve-fiber degeneration that were associated with increases in cerebrospinal fluid (CSF) and serum phosphorylated neurofilament heavy chain (pNF-H). RNA-sequencing analysis of DRGs showed that dysregulated pathways were preserved between NHPs and mice, including increases in innate/adaptive immune responses and decreases in mitochondrial- and neuronal-related genes, following AAV treatment. Finally, endogenous miR-21-5p was upregulated in DRGs of AAV-treated NHPs and mice. Increases in miR-21-5p were also identified within the CSF of NHPs, which significantly correlated with pNF-H, implicating miR-21-5p as a potential biomarker of DRG toxicity in conjunction with other molecular analytes. This work highlights the importance of assessing safety concerns related to DRG toxicity when developing RNAi-based AAV vectors for therapeutic purposes.
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