ArticleMolecular therapy : the journal of the American Society of Gene Therapy2014
Hyperactive piggyBac transposons for sustained and robust liver-targeted gene therapy.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed.
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- Current strategies employed in the manipulation of gene expression for clinical purposes.Journal of translational medicine · 2022Review
- Endoscopic-mediated, biliary hydrodynamic injection mediating clinically relevant levels of gene delivery in pig liver.Gastrointestinal endoscopy · 2021Article
- Conditioned CAR-T cells by hypoxia-inducible transcription amplification (HiTA) system significantly enhances systemic safety and retains antitumor efficacy.Journal for immunotherapy of cancer · 2021Article
- Novel vectors and approaches for gene therapy in liver diseases.JHEP reports : innovation in hepatology · 2021Review
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- Epigenetic suppression of SLFN11 in germinal center B-cells during B-cell development.PloS one · 2021Article
- Applications ofStem cells international · 2021Review
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- Validation of miR-20a as a Tumor Suppressor Gene in Liver Carcinoma Using Hepatocyte-Specific Hyperactive piggyBac Transposons.Molecular therapy. Nucleic acids · 2020Article
- In VivoInternational journal of molecular sciences · 2019Article
- Protein-Engineered Coagulation Factors for Hemophilia Gene Therapy.Molecular therapy. Methods & clinical development · 2019Review
- Next-generation muscle-directed gene therapy by in silico vector design.Nature communications · 2019Article
- Optimized Adeno-Associated Viral-Mediated Human Factor VIII Gene Therapy in Cynomolgus Macaques.Human gene therapy · 2018Article
- Autologous Cell Therapy Approach for Duchenne Muscular Dystrophy using PiggyBac Transposons and Mesoangioblasts.Molecular therapy : the journal of the American Society of Gene Therapy · 2018Article
Corrections and comments
- Commented on by
- Erratum issued
- Erratum issuedWaddingon, Simon N [corrected to Waddington, Simon N]
Authors and funding
8 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The development of robust nonviral vectors could facilitate clinical gene therapy applications and may overcome some of the immune complications of viral vectors. Nevertheless, most nonviral gene deliver approaches typically yield only transient and/or low gene expression. To address these caveats, we have explored piggyBac transposons to correct hemophilia B by liver-directed factor IX (FIX) gene therapy in hemophilic mice. To achieve this, we combined the use of: (i) a hyperactive codon-optimized piggyBac transposase, (ii) a computationally enhanced liver-specific promoter, (iii) a hyperfunctional codon-optimized FIX transgene (FIX R338L Padua), and (iv) a modification of the transposon terminal repeats. This combination strategy resulted in a robust 400-fold improvement in vector performance in hepatocytes, yielding stable supraphysiologic human FIX activity (>1 year). Liver-specific expression resulted in the induction of FIX-specific immune tolerance. Remarkably, only very low transposon/transposase doses were required to cure the bleeding diathesis. Similarly, PB transposons could be used to express supraphysiologic factor VIII levels using low transposon/transposase doses. PB transposition did not induce tumors in a sensitive hepatocellular carcinoma-prone mouse model. These results underscore the potency and relative safety of the latest generation PB transposons, which constitutes a versatile platform for stable and robust secretion of therapeutic proteins.
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