ArticleMolecular therapy. Methods & clinical development2024
Prenatal AAV9-GFP administration in fetal lambs results in transduction of female germ cells and maternal exposure to virus.
Article in Molecular therapy. Methods & clinical development, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Right ventricular pressure overload disturbs T-tubule maturation via MEF2D's transcriptional regulation of BIN1.JCI insight · 2026Article
- Ten years of disease-modifying therapy in spinal muscular atrophy: lessons learned and future directions.Nature reviews. Neurology · 2026Review
- Considerations for early life genetic therapies in cystic fibrosis.American journal of physiology. Lung cellular and molecular physiology · 2026Review
- Evaluation of Maternal Safety Following Prenatal Cell and Gene Therapy for Hemophilia A.Prenatal diagnosis · 2026Article
- The Expanding Role of Gene Sequencing in Shaping Fetal Therapies: Clinical and Ethical Considerations.Prenatal diagnosis · 2026Review
- Advancing AAV technology-From promise to product.Molecular therapy. Advances · 2026Article
- Evaluation of the Efficacy of Transglutaminase 1 Gene Delivery by Adeno-Associated Virus into Rat and Pig Skin and Safety of ARCI Gene Therapy.International journal of molecular sciences · 2025Article
- In utero therapy for spinal muscular atrophy: closer to clinical translation.Brain : a journal of neurology · 2025Review
- GFP-on mouse model for interrogation of in vivo gene editing.Nature communications · 2025Article
- In utero genetic therapy: Treatment of early onset neurological disorders before they start.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Advances in Fetal Surgery: A Narrative Review of Therapeutic Interventions and Future Directions.Medicina (Kaunas, Lithuania) · 2025Review
- Intra-amniotic antisense oligonucleotide treatment improves phenotypes in preclinical models of spinal muscular atrophy.Science translational medicine · 2025Article
- Prenatal gene editing for neurodevelopmental diseases: Ethical considerations.American journal of human genetics · 2025Review
- AAV viral vectors as therapeutic interventions for inherited or non-inherited cardiac disorders: current aspects and future prospects.Frontiers in medicine · 2025Review
Corrections and comments
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Authors and funding
17 authors.
Funding
Abstract
Prenatal somatic cell gene therapy (PSCGT) could potentially treat severe, early-onset genetic disorders such as spinal muscular atrophy (SMA) or muscular dystrophy. Given the approval of adeno-associated virus serotype 9 (AAV9) vectors in infants with SMA by the U.S. Food and Drug Administration, we tested the safety and biodistribution of AAV9-GFP (clinical-grade and dose) in fetal lambs to understand safety and efficacy after umbilical vein or intracranial injection on embryonic day 75 (E75) . Umbilical vein injection led to widespread biodistribution of vector genomes in all examined lamb tissues and in maternal uteruses at harvest (E96 or E140; term = E150). There was robust GFP expression in brain, spinal cord, dorsal root ganglia (DRGs), without DRG toxicity and excellent transduction of diaphragm and quadriceps muscles. However, we found evidence of systemic toxicity (fetal growth restriction) and maternal exposure to the viral vector (transient elevation of total bilirubin and a trend toward elevation in anti-AAV9 antibodies). There were no antibodies against GFP in ewes or lambs. Analysis of fetal gonads demonstrated GFP expression in female (but not male) germ cells, with low levels of integration-specific reads, without integration in select proto-oncogenes. These results suggest potential therapeutic benefit of AAV9 PSCGT for neuromuscular disorders, but warrant caution for exposure of female germ cells.
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