ArticleNature medicine2013
Endogenous factor VIII synthesis from the intron 22-inverted F8 locus may modulate the immunogenicity of replacement therapy for hemophilia A.
Article in Nature medicine, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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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.
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Who cites it
31 citing papers in PubMed, 68 citations in OpenAlex.
- Trial
- Isolated A1-domainResearch and practice in thrombosis and haemostasis · 2026Article
- Shaping hemophilia care: lessons and legacy of the SIPPET trial after 10 years.Research and practice in thrombosis and haemostasis · 2026Review
- Divergent processing of FVIII light chain variants: secretory potentialHaematologica · 2026Article
- Deleterious variants cluster in the A3 domain of factor VIII in people with severe hemophilia A and inhibitors.Research and practice in thrombosis and haemostasis · 2025Article
- A scan of pleiotropic immune mediated disease genes identifies novel determinants of baseline FVIII inhibitor status in hemophilia A.Genes and immunity · 2025Article
- Prediction of the chance of successful immune tolerance induction in persons with severe hemophilia A and inhibitors: a clinical prediction model.Research and practice in thrombosis and haemostasis · 2024Article
- Identification of the Efficient Enhancer Elements in FVIII-Padua for Gene Therapy Study of Hemophilia A.International journal of molecular sciences · 2024Article
- Article
- Hemophilia A subjects with an intron-22 gene inversion mutation show CD4Frontiers in immunology · 2023Article
- In vivo delivery of CRISPR-Cas9 using lipid nanoparticles enables antithrombin gene editing for sustainable hemophilia A and B therapy.Science advances · 2022Article
- Genome-Wide Association Study and Gene-Based Analysis of Participants With Hemophilia A and Inhibitors in the My Life, Our Future Research Repository.Frontiers in medicine · 2022Article
- Performance of a clinical risk prediction model for inhibitor formation in severe haemophilia A.Haemophilia : the official journal of the World Federation of Hemophilia · 2021Article
- The severe spontaneous bleeding phenotype in a novel hemophilia A rat model is rescued by platelet FVIII expression.Blood advances · 2020Article
- Further Evidence That MicroRNAs Can Play a Role in Hemophilia A Disease Manifestation:Frontiers in cell and developmental biology · 2020Article
- Specificity of the T Cell Response to Protein Biopharmaceuticals.Frontiers in immunology · 2020Review
- Peptides identified on monocyte-derived dendritic cells: a marker for clinical immunogenicity to FVIII products.Blood advances · 2019Article
- CD4 T cells specific for factor VIII are present at high frequency in healthy donors and comprise naïve and memory cells.Blood advances · 2017Article
- Advancing Public Health Using Regulatory Science to Enhance Development and Regulation of Medical Products: Food and Drug Administration Research at the Center for Biologics Evaluation and Research.Frontiers in medicine · 2017Review
- Gene therapy for immune tolerance induction in hemophilia with inhibitors.Journal of thrombosis and haemostasis : JTH · 2016Review
Corrections and comments
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Authors and funding
17 authors at 7 institutions in 4 countries.
Funding
Abstract
Neutralizing antibodies (inhibitors) to replacement factor VIII (FVIII, either plasma derived or recombinant) impair the effective management of hemophilia A. Individuals with hemophilia A due to major deletions of the FVIII gene (F8) lack antigenically cross-reactive material in their plasma ("CRM-negative"), and the prevalence of inhibitors in these individuals may be as high as 90%. Conversely, individuals with hemophilia A caused by F8 missense mutations are CRM-positive, and their overall prevalence of inhibitors is <10% (ref. 2). Individuals with the F8 intron 22 inversion (found in ∼50% of individuals with severe hemophilia A) have been grouped with the former on the basis of their genetic defect and CRM-negative status. However, only ∼20% of these individuals develop inhibitors. Here we demonstrate that the levels of F8 mRNA and intracellular FVIII protein in B lymphoblastoid cells and liver biopsies from individuals with the intron 22 inversion are comparable to those in healthy controls. These results support the hypothesis that most individuals with the intron 22 inversion are tolerized to FVIII and thus do not develop inhibitors. Furthermore, we developed a new pharmacogenetic algorithm that permits the stratification of inhibitor risk for individuals and subpopulations by predicting the immunogenicity of replacement FVIII using, as input, the number of putative T cell epitopes in the infused protein and the competence of major histocompatibility complex class II molecules to present such epitopes. This algorithm showed statistically significant accuracy in predicting the presence of inhibitors in 25 unrelated individuals with the intron 22 inversion.
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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.