ArticleHaematologica2021
Deciphering the Ets-1/2-mediated transcriptional regulation of F8 gene identifies a minimal F8 promoter for hemophilia A gene therapy.
Article in Haematologica, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8 citing papers in PubMed, 7 citations in OpenAlex.
- Isolated A1-domainResearch and practice in thrombosis and haemostasis · 2026Article
- Normothermic perfusion of human livers for profiling lentiviral vector pharmacokinetics and transduction.Molecular therapy. Advances · 2026Article
- Dissecting endothelial cell heterogeneity with new tools.Cell regeneration (London, England) · 2025Review
- GP64-pseudotyped lentiviral vectors target liver endothelial cells and correct hemophilia A mice.EMBO molecular medicine · 2024Article
- Identification of the Efficient Enhancer Elements in FVIII-Padua for Gene Therapy Study of Hemophilia A.International journal of molecular sciences · 2024Article
- Therapeutic potential of fetal liver cell transplantation in hemophilia A mice.Haematologica · 2023Article
- Heterogeneity and reciprocity of FVIII and VWF expression, and the response to shear stress in cultured human endothelial cells.Journal of thrombosis and haemostasis : JTH · 2022Article
- Factor VIII as a potential player in cancer pathophysiology.Journal of thrombosis and haemostasis : JTH · 2022Article
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A major challenge in the development of a gene therapy for hemophilia A (HA) is the selection of cell type- or tissue-specific promoters to ensure factor VIII (FVIII) expression without eliciting an immune response. As liver sinusoidal endothelial cells (LSECs) are the major FVIII source, understanding the transcriptional F8 regulation in these cells would help optimize the minimal F8 promoter (pF8) to efficiently drive FVIII expression. In silico analyses predicted several binding sites (BS) for the E26 transformation-specific (Ets) transcription factors Ets-1 and Ets-2 in the pF8. Reporter assays demonstrated a significant up-regulation of pF8 activity by Ets-1 or Ets-1/Est-2 combination, while Ets2 alone was ineffective. Moreover, Ets-1/Ets-2-DNA binding domain mutants (DBD) abolished promoter activation only when the Ets-1 DBD was removed, suggesting that pF8 up-regulation may occur through Ets-1/Ets-2 interaction with Ets-1 bound to DNA. pF8 carrying Ets-BS deletions unveiled two Ets-BS essential for pF8 activity and response to Ets overexpression. Lentivirus-mediated delivery of GFP or FVIII cassettes driven by the shortened promoters led to GFP expression mainly in endothelial cells in the liver and to long-term FVIII activity without inhibitor formation in HA mice. These data strongly support the potential application of these promoters in HA gene therapy.
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