ArticleMolecular therapy : the journal of the American Society of Gene Therapy2017
A Novel Platform for Immune Tolerance Induction in Hemophilia A Mice.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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40 citing papers in PubMed, 62 citations in OpenAlex.
- Unraveling Etiological Indications and Therapeutic Implications of Familial Cerebral Cavernous Malformations in the Dawn of Gene Therapy for Monogenic Conditions.Current gene therapy · 2025Article
- Rescue of the endogenous FVIII expression in hemophilia A mice using CRISPR-Cas9 mRNA LNPs.Molecular therapy. Nucleic acids · 2024Article
- Gene therapy of Dent disease type 1 in newborn ClC-5 null mice for sustained transgene expression and gene therapy effects.Gene therapy · 2024Article
- Roctavian gene therapy for hemophilia A.Blood advances · 2024Review
- Viral Vector Based Immunotherapy for Peanut Allergy.Viruses · 2024Review
- GP64-pseudotyped lentiviral vectors target liver endothelial cells and correct hemophilia A mice.EMBO molecular medicine · 2024Article
- Immune tolerance promotion by LSEC-specific lentiviral vector-mediated expression of the transgene regulated by the stabilin-2 promoter.Molecular therapy. Nucleic acids · 2024Article
- LSpECifying transgene expression.Molecular therapy. Nucleic acids · 2024Article
- Improved intravenous lentiviral gene therapy based on endothelial-specific promoter-driven factor VIII expression for hemophilia A.Molecular medicine (Cambridge, Mass.) · 2023Article
- Therapeutic potential of fetal liver cell transplantation in hemophilia A mice.Haematologica · 2023Article
- Lentiviral vector mediated gene therapy for type I Dent disease ameliorates Dent disease-like phenotypes for three months in ClC-5 null mice.Molecular therapy. Methods & clinical development · 2022Article
- Article
- Liver-directed lentiviral gene therapy corrects hemophilia A mice and achieves normal-range factor VIII activity in non-human primates.Nature communications · 2022Article
- Efficient and safe correction of hemophilia A by lentiviral vector-transduced BOECs in an implantable device.Molecular therapy. Methods & clinical development · 2021Article
- Deciphering the Ets-1/2-mediated transcriptional regulation of F8 gene identifies a minimal F8 promoter for hemophilia A gene therapy.Haematologica · 2021Article
- The hepcidin regulator erythroferrone is a new member of the erythropoiesis-iron-bone circuitry.eLife · 2021Article
- Gene Therapy for Inherited Bleeding Disorders.Seminars in thrombosis and hemostasis · 2021Review
- WFH State-of-the-art paper 2020: In vivo lentiviral vector gene therapy for haemophilia.Haemophilia : the official journal of the World Federation of Hemophilia · 2021Review
- Flow-Cytometry Platform for Intracellular Detection of FVIII in Blood Cells: A New Tool to Assess Gene Therapy Efficiency for Hemophilia A.Molecular therapy. Methods & clinical development · 2020Article
- Unexpected enhancement of FVIII immunogenicity by endothelial expression in lentivirus-transduced and transgenic mice.Blood advances · 2020Article
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12 authors at 4 institutions in 3 countries.
Funding
Abstract
Hemophilia A (HA) is an X-linked bleeding disease caused by factor VIII (FVIII) deficiency. We previously demonstrated that FVIII is produced specifically in liver sinusoid endothelial cells (LSECs) and to some degree in myeloid cells, and thus, in the present work, we seek to restrict the expression of FVIII transgene to these cells using cell-specific promoters. With this approach, we aim to limit immune response in a mouse model by lentiviral vector (LV)-mediated gene therapy encoding FVIII. To increase the target specificity of FVIII expression, we included miRNA target sequences (miRTs) (i.e., miRT-142.3p, miRT-126, and miRT-122) to silence expression in hematopoietic cells, endothelial cells, and hepatocytes, respectively. Notably, we report, for the first time, therapeutic levels of FVIII transgene expression at its natural site of production, which occurred without the formation of neutralizing antibodies (inhibitors). Moreover, inhibitors were eradicated in FVIII pre-immune mice through a regulatory T cell-dependent mechanism. In conclusion, targeting FVIII expression to LSECs and myeloid cells by using LVs with cell-specific promoter minimized off-target expression and immune responses. Therefore, at least for some transgenes, expression at the physiologic site of synthesis can enhance efficacy and safety, resulting in long-term correction of genetic diseases such as HA.
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