ArticleMolecular therapy. Methods & clinical development2022
Molecular analysis of AAV5-hFVIII-SQ vector-genome-processing kinetics in transduced mouse and nonhuman primate livers.
Article in Molecular therapy. Methods & clinical development, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 31 citations in OpenAlex.
- QSP model for AAV-mediated antibody delivery in rat brain.Journal of pharmacokinetics and pharmacodynamics · 2026Article
- rAAV8 encapsidated HMR-001/z enables high efficiency hepatic transduction and restores hemostasis in hemophilic mice.Gene therapy · 2026Article
- Translational insights from nonclinical studies of AAV gene therapies for hemophilia: mechanisms underpinning variability and durability of gene expression.Therapeutic advances in hematology · 2026Review
- Current Status of Clinical Gene Therapy for Hemophilia and Globin Disorders.Journal of blood medicine · 2026Review
- Cas9-Leveraged Single-Molecule Characterization of Sparse Plasmid Vectors in Heterogenous DNA Samples.Applied biochemistry and biotechnology · 2026Article
- Development of high-throughput analytical methods for characterization and quantitation of rAAV genome integrity.Molecular therapy. Methods & clinical development · 2025Article
- Characterization and quantitation of baculoviral DNA in rAAV vectors produced in Sf9 cells.Molecular therapy. Methods & clinical development · 2025Article
- AAV capsids target muscle-resident cells with different efficiencies-A comparative study between AAV8, AAVMYO, and AAVMYO2.Molecular therapy. Methods & clinical development · 2025Article
- Gene therapy for hemophilia - From basic science to first approvals of "one-and-done" therapies.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Roctavian gene therapy for hemophilia A.Blood advances · 2024Review
- Biological Barriers for Drug Delivery and Development of Innovative Therapeutic Approaches in HIV, Pancreatic Cancer, and Hemophilia A/B.Pharmaceutics · 2024Review
- The longitudinal kinetics of AAV5 vector integration profiles and evaluation of clonal expansion in mice.Molecular therapy. Methods & clinical development · 2024Article
- Pre-clinical evaluation of an enhanced-function factor VIII variant for durable hemophilia A gene therapy in male mice.Nature communications · 2024Article
- Analytical characterization of full, intermediate, and empty AAV capsids.Gene therapy · 2024Article
- Prophylactic Prednisolone Promotes AAV5 Hepatocyte Transduction Through the Novel Mechanism of AAV5 Coreceptor Platelet-Derived Growth Factor Receptor Alpha Upregulation and Innate Immune Suppression.Human gene therapy · 2024Article
- Stowaways in the cargo: Contaminating nucleic acids in rAAV preparations for gene therapy.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Review
- Vector genome loss and epigenetic modifications mediate decline in transgene expression of AAV5 vectors produced in mammalian and insect cells.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
- IL-15 blockade and rapamycin rescue multifactorial loss of factor VIII from AAV-transduced hepatocytes in hemophilia A mice.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
- Application ofMolecular therapy. Methods & clinical development · 2022Article
- Young mice administered adult doses of AAV5-hFVIII-SQ achieve therapeutic factor VIII expression into adulthood.Molecular therapy. Methods & clinical development · 2022Article
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Authors and funding
13 authors at 1 institution in 1 country.
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Abstract
Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-associated virus serotype 5 (AAV5)-based gene therapy vector containing a B-domain-deleted human coagulation factor VIII (hFVIII) gene controlled by a liver-selective promoter. AAV5-hFVIII-SQ is currently under clinical investigation as a treatment for severe hemophilia A. The full-length AAV5-hFVIII-SQ is >4.9 kb, which is over the optimal packaging limit of AAV5. Following administration, the vector must undergo a number of genome-processing, assembly, and repair steps to form full-length circularized episomes that mediate long-term FVIII expression in target tissues. To understand the processing kinetics of the oversized AAV5-hFVIII-SQ vector genome into circular episomes, we characterized the various molecular forms of the AAV5-hFVIII-SQ genome at multiple time points up to 6 months postdose in the liver of murine and non-human primate models. Full-length circular episomes were detected in liver tissue beginning 1 week postdosing. Over 6 months, quantities of circular episomes (in a predominantly head-to-tail configuration) increased, while DNA species lacking inverted terminal repeats were preferentially degraded. Levels of duplex, circular, full-length genomes significantly correlated with levels of hFVIII-SQ RNA transcripts in mice and non-human primates dosed with AAV5-hFVIII-SQ. Altogether, we show that formation of full-length circular episomes in the liver following AAV5-hFVIII-SQ transduction was associated with long-term FVIII expression.
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