ArticleThe Journal of biological chemistry2011
Enhanced biosynthesis of coagulation factor VIII through diminished engagement of the unfolded protein response.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 44 citations in OpenAlex.
- Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A.The New England journal of medicine · 2021Trial
- Defining the safety and efficacy of liver-directed AAV gene therapy using a human liver tissue-equivalent platform.Molecular therapy. Advances · 2026Article
- Article
- Hemophilia A: An Ideal Disease for Prenatal Therapy.Prenatal diagnosis · 2025Review
- Preclinical development of TAK-754, a high-performance AAV8-based vector expressing coagulation factor VIII.Molecular therapy. Methods & clinical development · 2025Article
- Lentiviral Gene Therapy with CD34+ Hematopoietic Cells for Hemophilia A.The New England journal of medicine · 2025Article
- Cellular stress and coagulation factor production: when more is not necessarily better.Journal of thrombosis and haemostasis : JTH · 2023Review
- Pharmacokinetic analysis identifies a factor VIII immunogenicity threshold after AAV gene therapy in hemophilia A mice.Blood advances · 2022Article
- Comparison of different gene addition strategies to modify placental derived-mesenchymal stromal cells to produce FVIII.Frontiers in immunology · 2022Article
- Non-genotoxic conditioning facilitates hematopoietic stem cell gene therapy for hemophilia A using bioengineered factor VIII.Molecular therapy. Methods & clinical development · 2021Article
- Molecular coevolution of coagulation factor VIII and von Willebrand factor.Blood advances · 2021Article
- Investigating Optimal Autologous Cellular Platforms for Prenatal or Perinatal Factor VIII Delivery to Treat Hemophilia A.Frontiers in cell and developmental biology · 2021Article
- Minimal Essential Human Factor VIII Alterations Enhance Secretion and Gene Therapy Efficiency.Molecular therapy. Methods & clinical development · 2020Article
- Defining the Optimal FVIII Transgene for Placental Cell-Based Gene Therapy to Treat Hemophilia A.Molecular therapy. Methods & clinical development · 2020Article
- Therapeutic Mesenchymal Stromal Cells for Immunotherapy and for Gene and Drug Delivery.Molecular therapy. Methods & clinical development · 2020Review
- The 3.2 Å structure of a bioengineered variant of blood coagulation factor VIII indicates two conformations of the C2 domain.Journal of thrombosis and haemostasis : JTH · 2020Article
- The Immune Response to the fVIII Gene Therapy in Preclinical Models.Frontiers in immunology · 2020Review
- Mechanistic Insights into Factor VIII Immune Tolerance Induction via Prenatal Cell Therapy in Hemophilia A.Current stem cell reports · 2019Article
- Protein-Engineered Coagulation Factors for Hemophilia Gene Therapy.Molecular therapy. Methods & clinical development · 2019Review
- Preclinical Development of a Hematopoietic Stem and Progenitor Cell Bioengineered Factor VIII Lentiviral Vector Gene Therapy for Hemophilia A.Human gene therapy · 2018Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Human and porcine coagulation factor VIII (fVIII) display a biosynthetic efficiency differential that is being exploited for the development of new protein and gene transfer-based therapies for hemophilia A. The cellular and/or molecular mechanism(s) responsible for this phenomenon have yet to be uncovered, although it has been temporally localized to post-translational biosynthetic steps. The unfolded protein response (UPR) is a cellular adaptation to structurally distinct (e.g. misfolded) or excess protein in the endoplasmic reticulum and is known to be induced by heterologous expression of recombinant human fVIII. Therefore, it is plausible that the biosynthetic differential between human and porcine fVIII results from differential UPR activation. In the current study, UPR induction was examined in the context of ongoing fVIII expression. UPR activation was greater during human fVIII expression when compared with porcine fVIII expression as determined by ER response element (ERSE)-luciferase reporter activity, X-box-binding protein 1 (XBP1) splicing, and immunoglobulin-binding protein (BiP) up-regulation. Immunofluorescence microscopy of fVIII expressing cells revealed that human fVIII was notably absent in the Golgi apparatus, confirming that endoplasmic reticulum to Golgi transport is rate-limiting. In contrast, a significant proportion of porcine fVIII was localized to the Golgi indicating efficient transit through the secretory pathway. Overexpression of BiP, an integral UPR protein, reduced the secretion of human fVIII by 50%, but had no effect on porcine fVIII biosynthesis. In contrast, expression of BiP shRNA increased human fVIII expression levels. The current data support the model of differential engagement of UPR by human and porcine fVIII as a non-traditional mechanism for regulation of gene product biosynthesis.
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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.