ArticleMolecular therapy : the journal of the American Society of Gene Therapy2017
In Utero Transfer of Adeno-Associated Viral Vectors Produces Long-Term Factor IX Levels in a Cynomolgus Macaque Model.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- Defining a Midgestational Window forbioRxiv : the preprint server for biology · 2026Article
- RAAVioli: A comprehensive approach to characterizing AAV vector integrations and rearrangements.Molecular therapy. Advances · 2026Article
- Transabdominal ultrasound guided AAV9-GFP delivery in fetal pigs: a translational and minimally invasive model for in utero fetal gene therapy.Gene therapy · 2025Article
- In utero therapy for spinal muscular atrophy: closer to clinical translation.Brain : a journal of neurology · 2025Review
- Rescue of the endogenous FVIII expression in hemophilia A mice using CRISPR-Cas9 mRNA LNPs.Molecular therapy. Nucleic acids · 2024Article
- Prenatal AAV9-GFP administration in fetal lambs results in transduction of female germ cells and maternal exposure to virus.Molecular therapy. Methods & clinical development · 2024Article
- Embryo and fetal gene editing: Technical challenges and progress toward clinical applications.Molecular therapy. Methods & clinical development · 2024Review
- Sustained and Efficient Delivery of Antivascular Endothelial Growth Factor by the Adeno-associated Virus for the Treatment of Corneal Neovascularization: An Outlook for Its Clinical Translation.Journal of ophthalmology · 2024Review
- Acceptability of prenatal diagnosis and prenatal treatment of haemophilia using cell and gene therapies within US haemophilia community.Haemophilia : the official journal of the World Federation of Hemophilia · 2023Article
- Intrathymic AAV delivery results in therapeutic site-specific integration at TCR loci in mice.Blood · 2023Article
- Gene modification therapies for hereditary diseases in the fetus.Prenatal diagnosis · 2023Review
- Premature delivery in the domestic sow in response to in utero delivery of AAV9 to fetal piglets.Gene therapy · 2022Article
- Prenatal Somatic Cell Gene Therapies: Charting a Path Toward Clinical Applications (Proceedings of the CERSI-FDA Meeting).Journal of clinical pharmacology · 2022Review
- Evaluating the state of the science for adeno-associated virus integration: An integrated perspective.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Review
- Catching Them Early: Framework Parameters and Progress for Prenatal and Childhood Application of Advanced Therapies.Pharmaceutics · 2022Review
- AAV integration in human hepatocytes.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
- A narrative review of in utero gene therapy: advances, challenges, and future considerations.Translational pediatrics · 2021Review
- Gene Therapy for Inherited Bleeding Disorders.Seminars in thrombosis and hemostasis · 2021Review
- Delivery technologies for in utero gene therapy.Advanced drug delivery reviews · 2021Review
- Liver-Targeted AAV8 Gene Therapy Ameliorates Skeletal and Cardiovascular Pathology in a Mucopolysaccharidosis IVA Murine Model.Molecular therapy. Methods & clinical development · 2020Article
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Authors and funding
13 authors.
Funding
Abstract
The safe correction of an inherited bleeding disorder in utero prior to the onset of organ damage is highly desirable. Here, we report long-term transgene expression over more than 6 years without toxicity following a single intrauterine gene transfer (IUGT) at 0.9G using recombinant adeno-associated vector (AAV)-human factor IX (hFIX) in the non-human primate model we have previously described. Four of six treated animals monitored for around 74 months expressed hFIX at therapeutic levels (3.9%-120.0%). Long-term expression was 6-fold higher in males and with AAV8 compared to AAV5, mediated almost completely at this stage by random genome-wide hepatic proviral integrations, with no evidence of hotspots. Post-natal AAV challenge without immunosuppression was evaluated in two animals exhibiting chronic low transgene expression. The brief neutralizing immune reaction elicited had no adverse effect and, although expression was not improved at the dose administered, no clinical toxicity was observed. This long-term surveillance thus confirms the safety of late-gestation AAV-hFIX transfer and demonstrates that postnatal re-administration can be performed without immunosuppression, although it requires dose optimization for the desired expression. Nevertheless, eventual vector genotoxicity and the possibility of germline transmission will require lifelong monitoring and further evaluation of the reproductive function of treated animals.
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