Delivery of Full-Length Factor VIII Using a piggyBac Transposon Vector to Correct a Mouse Model of Hemophilia A

Matsui, Hideto; Fujimoto, Naoko; Sasakawa, Nobuyuki; Ohinata, Yasuhide; Shima, Midori; Yamanaka, Shinya; Sugimoto, Mitsuhiko; Hotta, Akitsu

doi:10.1371/journal.pone.0104957

Cited by 46 publications

(41 citation statements)

References 43 publications

(10 reference statements)

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“…It has been demonstrated that PB transposons efficiently directed expression of insulin-like growth factor-1 receptor (IGF-1R) and glutathione transferase isozyme A4 (GSTA4) and subsequently attenuate renal fibrosis formation, one of the major deficient symptoms in mice with UUO. 159,160 In addition to wild-type PBase, 162 hyPBase system mediated long-term expression of blood clotting factor VIII (FVIII) and FIX and correct coagulation defects in hemophilia A and B mice, respectively. 59,62,163 Comparative analysis in the hemophilia B murine model indicated that the hyPBase was more efficient than mPBase, resulting in higher stable FIX expression levels.…”

Section: Hscmentioning

confidence: 99%

“…59,62 PB-mediated expression of FIX and FVIII was long lasting (>300 days) and did not induce an immunological reaction. 59,62,162 As a clinically feasible approach for transposonbased gene therapy, HD injection can be assisted by catheterization for local delivery of DNA in larger animal models such as pig, 164 dog, 165,166 and monkey. 60 It remains to be seen whether this method could eventually be applied safely and efficaciously in a clinical setting, given that hepatotoxicity ensued following HD injection.…”

Section: Hscmentioning

confidence: 99%

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Transposons: Moving Forward from Preclinical Studies to Clinical Trials

Tipanee¹,

VandenDriessche

Chuah

2017

Human Gene Therapy

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Transposons have emerged as promising vectors for gene therapy that can potentially overcome some of the limitations of commonly used viral vectors. Transposons stably integrate into the target cell genome, enabling persistent expression of therapeutic genes. Transposons have evolved from being used as basic tools in biomedical research to bona fide therapeutics. Currently, the most promising transposons for gene therapy applications are derived from Sleeping Beauty (SB) or piggyBac (PB). Stable transposition requires co-delivery of the transposon DNA with the corresponding transposase gene, mRNA, or protein. Stable transposition efficiency can be substantially increased by using "next-generation" transposon systems that combine codon-usage optimization with hyper-activating mutations in the SB or PB transposases. By virtue of their relatively large capacity, gene therapy applications with relatively large therapeutic transgenes, such as full-length dystrophin, can now be envisaged. The authors and others have shown that efficient and stable gene transfer can be achieved with these next-generation transposons in several clinically relevant primary cells, such as CD34 hematopoietic stem/progenitor cells, T cells, and mesenchymal and myogenic stem/progenitor cells that are amenable for ex vivo transfection. Alternatively, in vivo transposon gene delivery has been explored using non-viral vectors or nanoparticles or in combination with viral vectors. The therapeutic potential of these SB- and PB-based transposons has been demonstrated in preclinical models that mimic the cognate human diseases. However, there are still challenges impeding clinical translation of transposons pertaining mainly to the typical limiting efficiencies of most non-viral transfection methods and the intrinsic DNA toxicity. Nevertheless, it is particularly encouraging that transposons have now been used in gene therapy clinical trials. In particular, transposon-engineered T cells expressing chimeric antigen receptors are starting to yield promising results in patients with hematological malignancies.

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Section: Hscmentioning

confidence: 99%

Section: Hscmentioning

confidence: 99%

Transposons: Moving Forward from Preclinical Studies to Clinical Trials

Tipanee¹,

VandenDriessche

Chuah

2017

Human Gene Therapy

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“…More recently, investigators have demonstrated phenotypic correction of hemophilia A [52] and B [53] by piggyBac -mediated gene transfer to mouse liver. One report coupled the use of piggyBac with novel synthetic cell-type-specific promoters to improve efficiency of gene expression in vivo [53].…”

Section: In Vivo Gene Transfermentioning

confidence: 99%

piggyBac-ing models and new therapeutic strategies

Woodard

Wilson

2015

Trends in Biotechnology

101

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DNA transposons offer an efficient non-viral method of permanently modifying the genomes of mammalian cells. The piggyBac transposon system has proven effective in genomic engineering of mammalian cells for pre-clinical applications including gene discovery, simultaneous multiplexed genome modification, animal transgenesis, gene transfer in vivo achieving long-term gene expression in animals, and for genetic modification of clinically relevant cell types including induced pluripotent stem cells and human T lymphocytes. piggyBac has many desirable features including seamless excision of transposons from the genomic DNA and the potential to target integration events to desired DNA sequences. This review explores these recent applications and also highlights the unique advantages of using piggyBac for developing new molecular therapeutic strategies.

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“…Already hydrodynamic injection of CRISPR/Cas9 plasmids has been shown to correct the metabolic liver disease hereditary tyrosinemia in mice. 134 Other forms of nonviral in vivo delivery, such as ultrasound with microbubbles, cationic lipid complexes, and DNA nanoparticles, have been investigated. [135][136][137] Given the pace of advances, even in vivo delivery of genome editing reagents targeted directly to hematopoietic cells including HSCs seems conceivable.…”

Section: Deliverymentioning

confidence: 99%

A genome editing primer for the hematologist

Hoban

Bauer

2016

Blood

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Gene editing enables the site-specific modification of the genome. These technologies have rapidly advanced such that they have entered common use in experimental hematology to investigate genetic function. In addition, genome editing is becoming increasingly plausible as a treatment modality to rectify genetic blood disorders and improve cellular therapies. Genome modification typically ensues from site-specific double-strand breaks and may result in a myriad of outcomes. Even single-strand nicks and targeted biochemical modifications that do not permanently alter the DNA sequence (epigenome editing) may be powerful instruments. In this review, we examine the various technologies, describe their advantages and shortcomings for engendering useful genetic alterations, and consider future prospects for genome editing to impact hematology.

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Delivery of Full-Length Factor VIII Using a piggyBac Transposon Vector to Correct a Mouse Model of Hemophilia A

Cited by 46 publications

References 43 publications

Transposons: Moving Forward from Preclinical Studies to Clinical Trials

Transposons: Moving Forward from Preclinical Studies to Clinical Trials

piggyBac-ing models and new therapeutic strategies

A genome editing primer for the hematologist

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