ArticleNature medicine2022
Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A.
Article in Nature medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02576795 (A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of Valoctocogene Roxaparvovec, an Adenovirus-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Patients With Severe Haemophilia A), which is not on this map. Cited by 67 papers, 2 of them syntheses that pooled it.
What it found
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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.
The trial behind it
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.
A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of Valoctocogene Roxaparvovec, an Adenovirus-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Patients With Severe Haemophilia A
Who cites it
67 citing papers in PubMed, 2 syntheses or guidelines pooled it, 106 citations in OpenAlex.
- Liver-related aspects of valoctocogene roxaparvovec gene therapy for hemophilia A: expert guidance for clinical practice.Blood advances · 2024Guideline
- A systematic review of immunosuppressive protocols used in AAV gene therapy for monogenic disorders.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Pooled it
- Durability of efficacy, safety, and quality of life 5 years after valoctocogene roxaparvovec gene transfer for severe hemophilia A: final phase 3 GENEr8-1 trial results.Research and practice in thrombosis and haemostasis · 2026Trial
- A phase 1/2 safety and efficacy study of TAK-754 gene therapy: The challenge of achieving durable factor VIII expression in haemophilia A clinical trials.Haemophilia : the official journal of the World Federation of Hemophilia · 2025Trial
- Blood biodistribution and vector shedding of valoctocogene roxaparvovec in people with severe hemophilia A.Blood advances · 2024Trial
- Final Analysis of the Phase 1/2 Trial of Valoctocogene Roxaparvovec for Severe Haemophilia A.Haemophilia : the official journal of the World Federation of HemophiliaTrial
- Clinical immunogenicity in rAAV gene therapy: Insights and implications.Molecular therapy. Advances · 2026Review
- Distinct YY dinucleotide periodicity in adeno-associated virus DNA.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Hydrogel Microtube Drug Carrier for Catheter-Based Intravascular Therapy.Advanced healthcare materials · 2026Article
- Roctavian withdrawal: exploring the gap between innovation and healthcare system readiness in hemophilia A gene therapy.Research and practice in thrombosis and haemostasis · 2026Review
- Development of an Agent-Based Model to Investigate Durability of Factor IX Activity in Hemophilia B Patients Treated With Etranacogene Dezaparvovec.CPT: pharmacometrics & systems pharmacology · 2026Article
- Reprogramming innate immunity through viral interference: A double-edged strategy for enhancing and containing gene therapies.Molecular therapy. Nucleic acids · 2026Review
- Transforming Hemophilia Management: Lessons from Gene Therapy Clinical Trials.Molecular biotechnology · 2026Review
- Article
- Current Status of Clinical Gene Therapy for Hemophilia and Globin Disorders.Journal of blood medicine · 2026Review
- Translational insights from nonclinical studies of AAV gene therapies for hemophilia: mechanisms underpinning variability and durability of gene expression.Therapeutic advances in hematology · 2026Review
- Article
- GH-resistant (Laron) mice: gene therapy with a liver-specific GH receptor causes unbalanced upregulation of female-biased and growth-related genes.Frontiers in endocrinology · 2026Article
- AAV capsid prioritization in normal and steatotic human livers maintained by machine perfusion.Nature biotechnology · 2025Article
- AAV vectors tested in perfused human livers.Nature biotechnology · 2025Article
7 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
15 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Factor VIII gene transfer with a single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ) has demonstrated clinical benefits lasting 5 years to date in people with severe hemophilia A. Molecular mechanisms underlying sustained AAV5-hFVIII-SQ-derived FVIII expression have not been studied in humans. In a substudy of the phase 1/2 clinical trial ( NCT02576795 ), liver biopsy samples were collected 2.6-4.1 years after gene transfer from five participants. Primary objectives were to examine effects on liver histopathology, determine the transduction pattern and percentage of hepatocytes transduced with AAV5-hFVIII-SQ genomes, characterize and quantify episomal forms of vector DNA and quantify transgene expression (hFVIII-SQ RNA and hFVIII-SQ protein). Histopathology revealed no dysplasia, architectural distortion, fibrosis or chronic inflammation, and no endoplasmic reticulum stress was detected in hepatocytes expressing hFVIII-SQ protein. Hepatocytes stained positive for vector genomes, showing a trend for more cells transduced with higher doses. Molecular analysis demonstrated the presence of full-length, inverted terminal repeat-fused, circular episomal genomes, which are associated with long-term expression. Interindividual differences in transgene expression were noted despite similar successful transduction, possibly influenced by host-mediated post-transduction mechanisms of vector transcription, hFVIII-SQ protein translation and secretion. Overall, these results demonstrate persistent episomal vector structures following AAV5-hFVIII-SQ administration and begin to elucidate potential mechanisms mediating interindividual variability.
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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.