ArticleMolecular therapy : the journal of the American Society of Gene Therapy2023
Liver injury in cynomolgus monkeys following intravenous and intrathecal scAAV9 gene therapy delivery.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 43 citations in OpenAlex.
- Next generation AAV-F capsid gene therapy rescues disease pathology in a model of pyruvate dehydrogenase complex deficiency.Molecular therapy. Advances · 2026Article
- Adeno-Associated Virus Gene Therapy for Spinal Muscular Atrophy Induces Hepatotoxicity via Cytokine and Macrophage Activation.Liver international : official journal of the International Association for the Study of the Liver · 2026Article
- AAV Vector Toolkit for the Delivery and Expression of the Artificial microRNA in the Murine Heart.Biotech (Basel (Switzerland)) · 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
- Long-term comparative analysis of AAV9-mediated gene replacement therapies for spinal muscular atrophy in mice.Nature communications · 2026Article
- Metadata assessment of non-human primate studies of AAV9 uncovers potential tissue specific variation in expression efficiency.Gene therapy · 2026Article
- Deaths in gene therapy of Duchenne muscular dystrophy and other diseases: Underlying mechanisms and mitigating strategies.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Review
- Preclinical evaluation of INS1201 AAV9-micro-dystrophin via CSF administration as a potential therapy for Duchenne muscular dystrophy.Molecular therapy. Advances · 2026Article
- DNA damage/p53, innate immune, and unfolded protein responses are activated in primate liver after toxic, high-dose AAV-SMN1 delivery.Molecular therapy. Advances · 2026Article
- Comparison of AAV9-driven motor neuron transduction following different CNS-directed delivery methods in mice.Scientific reports · 2026Article
- AAV-mediated gene therapy for Alzheimer's disease: neuroprotective mechanisms and translational challenges.Frontiers in aging neuroscience · 2026Review
- Delivery platforms forFrontiers in immunology · 2026Review
- CMTM6/PD-L1-targeted AAV promotes anti-tumor immune responses and chemotherapy responsiveness.Frontiers in immunology · 2026Article
- 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
- Directed evolution of liver-detargeted AAV vectors for systemic gene delivery to skeletal muscle and heart.Molecular therapy. Methods & clinical development · 2025Article
- An AAV-Based Therapy Approach for Neurological Phenotypes of X-Linked Adrenoleukodystrophy.International journal of molecular sciences · 2025Review
- Advances in gene therapy for Lafora disease: Intravenous recombinant adeno-associated virus-mediated delivery of EPM2A and EPM2B genes.Clinical and translational medicine · 2025Article
- Directed evolution of novel AAV variants using the MCMS library for enhanced CNS tropism and reduced liver targeting in mice.Molecular therapy. Methods & clinical development · 2025Article
- Innate immune response to AAV-based gene therapy vectors: Mechanisms of complement activation and cytokine release.Molecular therapy. Methods & clinical development · 2025Article
- A single amino acid variant in the variable region I of AAV capsid confers liver detargeting.PLoS pathogens · 2025Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hepatotoxicity associated with intravenous/intrathecal adeno-associated virus (AAV) gene therapy has been observed in preclinical species and patients. In nonhuman primates, hepatotoxicity following self-complementary AAV9 administration varies from asymptomatic transaminase elevation with minimal to mild microscopic changes to symptomatic elevations of liver function and thromboinflammatory markers with microscopic changes consistent with marked hepatocellular necrosis and deteriorating clinical condition. These transient acute liver injury marker elevations occur from 3-4 days post intravenous administration to ∼2 weeks post intrathecal administration. No transaminase elevation or microscopic changes were observed with intrathecal administration of empty capsids or a "promoterless genome" vector, suggesting that liver injury after cerebrospinal fluid dosing in nonhuman primates is driven by viral transduction and transgene expression. Co-administration of prednisolone after intravenous or intrathecal dosing did not prevent liver enzyme or microscopic changes despite a reduction of T lymphocyte infiltration in liver tissue. Similarly, co-administration of rituximab/everolimus with intrathecal dosing failed to block AAV-driven hepatotoxicity. Self-complementary AAV-induced acute liver injury appears to correlate with high hepatocellular vector load, macrophage activation, and type 1 interferon innate virus-sensing pathway responses. The current work characterizes key aspects pertaining to early AAV-driven hepatotoxicity in cynomolgus macaques, highlighting the usefulness of this nonclinical species in that context.
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