ArticleNature neuroscience2021
Gain of toxic function by long-term AAV9-mediated SMN overexpression in the sensorimotor circuit.
Article in Nature neuroscience, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 130 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
130 citing papers in PubMed, 1 synthesis or guideline pooled it, 189 citations in OpenAlex.
- Systematic review and meta-analysis determining the benefits of in vivo genetic therapy in spinal muscular atrophy rodent models.Gene therapy · 2022Pooled it
- Intrathecal onasemnogene abeparvovec in treatment-naive patients with spinal muscular atrophy: a phase 3, randomized controlled trial.Nature medicine · 2026Trial
- Nusinersen: the antisense oligonucleotide at the forefront of spinal muscular atrophy treatment.RNA biology · 2026Review
- Programmable enzymes for targeted gene insertion.Nature reviews. Genetics · 2026Review
- Lack of sensorimotor toxicity when using the clinical SMN expression cassette in scAAV9.Nature neuroscience · 2026Article
- Challenging the more-is-better dogma: A precision-optimized AAV gene therapy for SMA.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- A p53-ΔNp73 signaling axis drives selective motor neuron degeneration in spinal muscular atrophy.bioRxiv : the preprint server for biology · 2026Article
- Intrathecal (GActa neuropathologica communications · 2026Article
- Review
- Long-term comparative analysis of AAV9-mediated gene replacement therapies for spinal muscular atrophy in mice.Nature communications · 2026Article
- KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS.JCI insight · 2026Article
- Article
- Testicular mRNA-LNP Delivery: A Novel Therapy for Genetic Spermatogenic Disorders.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Mechanisms linking cytoplasmic decay of translation-defective mRNA to transcriptional adaptation.Science (New York, N.Y.) · 2026Article
- Intrathecal (GbioRxiv : the preprint server for biology · 2026Article
- A Head-to-Head Comparison of AAV9 Biodistribution in Mice: Routes of Administration and Age Dependence.Genes · 2026Article
- Polyserine domains are toxic and exacerbate tau pathology in mice.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- AAV9 gene therapy optimization for SMARD1/CMT2S: safety and long-term efficacy comparison of two vectors in a SMARD1 preclinical model.Journal of biomedical science · 2026Article
- A therapeutic antisense oligonucleotide encompassing 2'-NAR molecular medicine · 2026Article
- The survival motor neuron protein: structure, functions, stability, and therapeutic targeting.Frontiers in cellular neuroscience · 2026Review
70 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
The neurodegenerative disease spinal muscular atrophy (SMA) is caused by deficiency in the survival motor neuron (SMN) protein. Currently approved SMA treatments aim to restore SMN, but the potential for SMN expression beyond physiological levels is a unique feature of adeno-associated virus serotype 9 (AAV9)-SMN gene therapy. Here, we show that long-term AAV9-mediated SMN overexpression in mouse models induces dose-dependent, late-onset motor dysfunction associated with loss of proprioceptive synapses and neurodegeneration. Mechanistically, aggregation of overexpressed SMN in the cytoplasm of motor circuit neurons sequesters components of small nuclear ribonucleoproteins, leading to splicing dysregulation and widespread transcriptome abnormalities with prominent signatures of neuroinflammation and the innate immune response. Thus, long-term SMN overexpression interferes with RNA regulation and triggers SMA-like pathogenic events through toxic gain-of-function mechanisms. These unanticipated, SMN-dependent and neuron-specific liabilities warrant caution on the long-term safety of treating individuals with SMA with AAV9-SMN and the risks of uncontrolled protein expression by gene therapy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.