Steps Toward Safe Cell Therapy Using Induced Pluripotent Stem Cells

Okano, Hideyuki; Nakamura, Masaya; Yoshida, Kenji; Okada, Yohei; Tsuji, Osahiko; Nori, Satoshi; Ikeda, Eiji; Yamanaka, Shinya; Miura, Kyoko

doi:10.1161/circresaha.111.256149

Cited by 380 publications

(304 citation statements)

References 90 publications

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“…Recently, research on this problem has rapidly progressed, and many studies have proposed solutions [40], including establishment of iPS cells with transient gene expression instead of using retroviruses or lentiviruses [38,[41][42][43], by introducing proteins [44][45][46], by substituting some genes with drugs [44,46] and by using minicircle vectors that enable longer-term gene expression than plasmid vectors [47]. According to the results of our previous studies, transgene reactivation npg and incomplete reprograming are considered as the main causes of tumorigenesis, and we propose to use integration-free iPS cells reprogramed using episomal vectors in the future to overcome the first of these problems [40,48]. Furthermore, among our most important tasks before successful clinical application will be to induce Glis-1-transduced iPS cells, developed by Yamanaka et al [49], which are reprogramed more completely, this allowing them to differentiate reliably into NS/PCs, and to accurately evaluate the safety of this final product.…”

Section: Future Problems and Perspectivementioning

confidence: 99%

“…Furthermore, among our most important tasks before successful clinical application will be to induce Glis-1-transduced iPS cells, developed by Yamanaka et al [49], which are reprogramed more completely, this allowing them to differentiate reliably into NS/PCs, and to accurately evaluate the safety of this final product. In addition to these improvements of the iPS cells, the safety issues must be validated through the intensive quality examination of iPS cell-derived NS/PCs in terms of genetic and epigenetic status, and their differentiation, proliferation and tumorigenicity In vivo, prior to the first human trials [40]. Finally, another important challenge before attempting clinical application pertains to the use of agents and cells derived from xenogeneic sources.…”

Section: Future Problems and Perspectivementioning

confidence: 99%

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Cell transplantation therapies for spinal cord injury focusing on induced pluripotent stem cells

2012

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Section: Future Problems and Perspectivementioning

confidence: 99%

Section: Future Problems and Perspectivementioning

confidence: 99%

Cell transplantation therapies for spinal cord injury focusing on induced pluripotent stem cells

2012

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“…97 time, there are significant limitations to the use of iPSCs including slow propagation, concerns for incomplete reprogramming, immunogenicity and potential tumourigenesis. 98 Currently, there is a proposed human trial of iPSCs in Japan in which six patients with exudative age-related macular degeneration will have autologous iPSC-generated retinal pigment epithelial sheath transplantation (please see http://www. riken-ibri.jp/AMD/english/research/index.html).…”

Section: Dmd = Disease-modifying Drug; Ipsc = Induced Pluripotent Stementioning

confidence: 99%

Cell-Based Therapeutic Strategies in Multiple Sclerosis

Rossman

Cohen²

2014

European Neurological Review

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Multiple sclerosis (MS) is an immune-mediated disease in which acute inflammatory demyelination leads to axonal injury and neurodegeneration, and is manifested clinically by relapsing-remitting neurological deficits superimposed on chronic accumulation of disability. MS treatments are largely immunomodulatory with little, if any, effect on neurodegeneration. Mesenchymal stem cells (MSCs) are pluripotent cells derived from adult tissues with intrinsic anti-inflammatory and repair-promoting properties. They cross the blood-brain barrier and target perivascular spaces, which are the sites of inflammatory cell infiltration in MS. In vitro, MSCs can be purified and expanded, labelled for post-transplant tracking and be manipulated to express surface receptors or neurotrophic factors for central nervous system (CNS) targeting or neuroprotection, respectively. Animal models of MS, traumatic CNS injury and neurodegenerative diseases demonstrate clinical and pathological benefits following MSC transplantation. Potentially, MSCs can be used to treat MS patients at various disease stages, which is the current focus of ongoing phase I/II clinical trials at multiple centres. KeywordsMultiple sclerosis, mesenchymal stem cell, clinical trial, induced pluripotent stem cell, experimental autoimmune encephalitis exposure and smoking, and these likely interact heterogeneously with genetic factors across the MS population. 5,6 Thus, the natural history of MS varies between patients. The average age of onset is typically in the third decade and there is a peak prevalence in the fifth decade of life. Paediatric MS is rarer, particularly in patients aged younger than 9 years of age, though there is a growing recognition of early-onset MS and its implications for earlier disability than adult-onset MS. 4,7,8 The prevalence of MS has been estimated at one to two per 1,000 in North America and northern Europe, but the incidence and prevalence vary geographically, seem to increase with latitude and appear to be increasing, particularly in women.9 A systematic review of the financial burden of MS in the US found a range of $8,528-54,244 per patient per year, with approximately 77 % representing direct costs to the patient (i.e. prescription medications), making MS the second most costly disease in the US behind congestive heart failure. Current Treatments in Relapsing-Remitting Multiple SclerosisThe mainstay of MS therapy has been anti-inflammatory diseasemodifying drugs (DMDs) that target various immune system pathways to decrease or prevent the continuation of an immune-mediated destructive process. 4 In the clinical context, the goal of therapy is twofold: 1) minimising accumulated disability associated with clinical relapses; and 2) preventing the MRI lesion activity, which can occur in the absence of clinical symptoms. The mechanisms of action, route of delivery, safety, tolerability and side-effect profiles differ between DMDs, though they all serve these two principles. Thus, DMD treatment should be considered early follow...

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“…Previous studies have demonstrated that NS/PC transplantation promotes functional recovery in spinal cord injury (SCI) animal models, prompting several investigators to proceed to clinical applications [4][5][6][7][8][9][10]. Some clinical trials responses between rodents and primates [12,13].…”

Section: Introductionmentioning

confidence: 99%

Allogeneic Neural Stem/Progenitor Cells Derived From Embryonic Stem Cells Promote Functional Recovery After Transplantation Into Injured Spinal Cord of Nonhuman Primates

Iwai

Shimada

Nishimura

et al. 2015

Stem Cells Translational Medicine

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Previous studies have demonstrated that neural stem/progenitor cells (NS/PCs) promote functional recovery in rodent animal models of spinal cord injury (SCI). Because distinct differences exist in the neuroanatomy and immunological responses between rodents and primates, it is critical to determine the effectiveness and safety of allografted embryonic stem cell (ESC)-derived NS/PCs (ESC-NS/PCs) in a nonhuman primate SCI model. In the present study, common marmoset ESC-NS/PCs were grafted into the lesion epicenter 14 days after contusive SCI in adult marmosets (transplantation group). In the control group, phosphate-buffered saline was injected instead of cells. In the presence of a low-dose of tacrolimus, several grafted cells survived without tumorigenicity and differentiated into neurons, astrocytes, or oligodendrocytes. Significant differences were found in the transverse areas of luxol fast blue-positive myelin sheaths, neurofilament-positive axons, corticospinal tract fibers, and platelet endothelial cell adhesion molecule-1-positive vessels at the lesion epicenter between the transplantation and control groups. Immunoelectron microscopic examination demonstrated that the grafted ESC-NS/PC-derived oligodendrocytes contributed to the remyelination of demyelinated axons. In addition, some grafted neurons formed synaptic connections with host cells, and some transplanted neurons were myelinated by host cells. Eventually, motor functional recovery significantly improved in the transplantation group compared with the control group. In addition, a mixedlymphocyte reaction assay indicated that ESC-NS/PCs modulated the allogeneic immune rejection. Taken together, our results indicate that allogeneic transplantation of ESC-NS/PCs from a nonhuman primate promoted functional recovery after SCI without tumorigenicity. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:708-719 SIGNIFICANCEThis study demonstrates that allogeneic embryonic stem cell (ESC)-derived neural stem/progenitor cells (NS/PCs) promoted functional recovery after transplantation into the injured spinal cord in nonhuman primates. ESC-NS/PCs were chosen because ESC-NS/PCs are one of the controls for induced pluripotent stem cell-derived NS/PCs and because ESC derivatives are possible candidates for clinical use. This translational research using an allograft model of a nonhuman primate is critical for clinical application of grafting NS/PCs derived from various allogeneic pluripotent stem cells, especially induced pluripotent stem cells, into injured spinal cord at the subacute phase.

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Steps Toward Safe Cell Therapy Using Induced Pluripotent Stem Cells

Cited by 380 publications

References 90 publications

Cell transplantation therapies for spinal cord injury focusing on induced pluripotent stem cells

Cell transplantation therapies for spinal cord injury focusing on induced pluripotent stem cells

Cell-Based Therapeutic Strategies in Multiple Sclerosis

Allogeneic Neural Stem/Progenitor Cells Derived From Embryonic Stem Cells Promote Functional Recovery After Transplantation Into Injured Spinal Cord of Nonhuman Primates

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