Therapeutic effects of induced pluripotent stem cells in chimeric mice with  -thalassemia

Yang, Guangzheng; Shi, Wansheng; Hu, Xingyin; Zhang, Jingzhi; Gong, Zhijuan; Guo, Xia; Ren, Zhaorui; Zeng, Fanyi

doi:10.3324/haematol.2013.087916

Cited by 12 publications

(15 citation statements)

References 49 publications

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“…We suggest that the therapeutic effect of FOE-treated fibroblasts would improve if more FOE-treated fibroblasts were transplanted or if purified iMS cells derived from FOE-treated fibroblasts were transplanted. In fact, iPS cells have demonstrated dose-dependent stable therapeutic effects in chimeric mice with beta-thalassemia [17]. Human dystrophin expression in FOE-treated fibroblast-transplanted mdx mice was detected, indicating that reprogrammed cells were present, and such cells expressed multipotent markers, integrated into the injury site, and expressed dystrophin in mice.…”

Section: Discussionmentioning

confidence: 95%

In vitro and in vivo analysis of human fibroblast reprogramming and multipotency

Pang

Zhu

Geng

et al. 2015

Cellular and Molecular Biology Letters

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Multipotent stem cells have potential therapeutic roles in the treatment of Duchenne muscular dystrophy (DMD). However, the limited access to stem cell sources restricts their clinical application. To address this issue, we established a simple in vitro epigenetic reprogramming technique in which skin fibroblasts are induced to dedifferentiate into multipotent cells. In this study, human fibroblasts were isolated from circumcised adult foreskin and were reprogrammed by co-culture for 72 h with fish oocyte extract (FOE) in serum-free medium. The cells were then observed and analyzed by immunofluorescence staining, flow cytometry and in vitro differentiation assays. Then FOE-treated human fibroblasts were transplanted by tail vein injection into irradiated mdx mice, an animal model of DMD. Two months after injection, the therapeutic effects of FOE-treated fibroblasts on mdx skeletal muscle were evaluated by serum creatine kinase (CK) activity measurements and by immunostaining and RT-PCR of human dystrophin expression. The results indicated that the reprogrammed fibroblasts expressed higher levels of the pluripotent antigen markers SSEA-4, Nanog and Oct-4, and were able to differentiate in vitro into adipogenic cells, osteoblastic cells, and myotube-like cells. Tail vein injection of FOE-treated fibroblasts into irradiated mdx mice slightly reduced serum CK activity and the percentage of centrally nucleated myofibers two months after cell transplantation. Furthermore, we confirmed human dystrophin protein and mRNA expression in mdx mouse skeletal muscle. These data demonstrated that FOE-treated fibroblasts were multipotent and could integrate into mdx mouse myofibers through the vasculature.

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Section: Discussionmentioning

confidence: 95%

In vitro and in vivo analysis of human fibroblast reprogramming and multipotency

Pang

Zhu

Geng

et al. 2015

Cellular and Molecular Biology Letters

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“…Human iPSCs obtained from this patient were able to differentiate into hematopoietic cells that synthesized fetal Hb in vitro, thus raising the possibility of using iPSCs to treat patients with homozygous β-thalassemia [42]. vectors set the stage for its application in clinical settings [45]. Cavazzano et al reported one effective case in a phase I/II clinical trial, but several recently published studies showed that these approaches remained rather inefficient [45].…”

Section: Thalassemiamentioning

confidence: 99%

“…vectors set the stage for its application in clinical settings [45]. Cavazzano et al reported one effective case in a phase I/II clinical trial, but several recently published studies showed that these approaches remained rather inefficient [45]. Therapies using iPSCs combined with transgenes can potentially cure thalassemia in the future, but obstacles such as safety, efficacy and cell stability remain to be solved.…”

Section: Thalassemiamentioning

confidence: 99%

“…A state of mixed chimerism is usually detected after transplantation and often progresses towards complete chimerism after HSCT for thalassemia. This implies that thalassemia can be controlled with appropriate doses of HSCs [45]. However, effective postnatal therapy with autologous modified iPSCs may require engineered expression of normal β-globin and chimerism levels exceeding 20% [45].…”

Section: Thalassemiamentioning

confidence: 99%

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Induced Pluripotent Stem Cells and Their Future Therapeutic Applications in Hematology

Al-Anazi¹

2015

J Stem Cell Res Ther

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Reprogramming of iPSCs should have the following requirements: (1) species such as humans or mice, (2) cell type such as fibroblasts or blood cells, (3) factor or chemical such as protein, gene or valproic acid, (4) vector such as retrovirus or lentivirus, and (5) diseases with specific genetic mutations [6,7,9]. DNA and non-DNA methods have been employed in induction and programming of iPSCs (Table 4) [4-9]. The following genes have been used in inducing PSCs: Oct 3/4, Sox2, Klf4, C-Myc, Nanog, LIN 28, Glis 1 and REX 1 [3,4,7]. Also, a long list of agents or vectors have been used in iPSC programming and these include: single or multiple transient transfections, excisable and nonintegrating vectors, proteins and direct protein transduction, plasmid and episomal vectors, minicircle DNA, modified RNA, RNA-based Sendai viruses, mRNA-based transcription factor delivery, microRNA transfections, artificial chromosome vectors, chemical compounds and small molecule compounds. These agents have been reported to improve safety and efficacy of the reprogramming process [5,7]. Small molecule compounds have recently been utilized to generate mouse iPSCs from

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“…Combining ex vivo gene transfer with iPSC may have high potential for the treatment of a number of genetic disorders. For example, transducing iPSC with a functional copy of β-globin gene showed promising results both in the treatment of β-thalassemia whether in in vitro ( 51 ) and in in vivo models ( 52 ). However, further studies are needed on this topic as it has been shown that iPSC may implicate some unacceptable safety risks in clinical application.…”

Section: Gene Therapy Medicinal Productsmentioning

confidence: 99%

Regulatory and Scientific Advancements in Gene Therapy: State-of-the-Art of Clinical Applications and of the Supporting European Regulatory Framework

2017

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Advanced therapy medicinal products (ATMPs) have a massive potential to address existing unmet medical needs. Specifically, gene therapy medicinal products (GTMPs) may potentially provide cure for several genetic diseases. In Europe, the ATMP regulation was fully implemented in 2009 and, at this point, the Committee for Advanced Therapies was created as a dedicated group of specialists to evaluate medicinal products requiring specific expertise in this area. To date, there are three authorized GTMPs, and the first one was approved in 2012. Broad research has been conducted in this field over the last few decades and different clinical applications are being investigated worldwide, using different strategies that range from direct gene replacement or addition to more complex pathways such as specific gene editing or RNA targeting. Important safety risks, limited efficacy, manufacturing hurdles, or ethical conflicts may represent challenges in the success of a candidate GTMP. During the development process, it is fundamental to take such aspects into account and establish overcoming strategies. This article reviews the current European legal framework of ATMPs, provides an overview of the clinical applications for approved and investigational GTMPs, and discusses critical challenges in the development of GTMPs.

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Therapeutic effects of induced pluripotent stem cells in chimeric mice with -thalassemia

Abstract: chimeric murine models to evaluate the in vivo efficacy, safety, and stability of treatment with β hu -β 654 iPSCs (β 654

Cited by 12 publications

References 49 publications

In vitro and in vivo analysis of human fibroblast reprogramming and multipotency

In vitro and in vivo analysis of human fibroblast reprogramming and multipotency

Induced Pluripotent Stem Cells and Their Future Therapeutic Applications in Hematology

Regulatory and Scientific Advancements in Gene Therapy: State-of-the-Art of Clinical Applications and of the Supporting European Regulatory Framework

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