Therapeutic cloning in individual Parkinsonian mice

Department of Neurosurgery, Sloan-Kettering Institute, 1275 York Ave, New York, New York 10065, USA.
Nature medicine (Impact Factor: 27.36). 05/2008; 14(4):379-81. DOI: 10.1038/nm1732
Source: PubMed


Cell transplantation with embryonic stem (ES) cell progeny requires immunological compatibility with host tissue. 'Therapeutic cloning' is a strategy to overcome this limitation by generating nuclear transfer (nt)ES cells that are genetically matched to an individual. Here we establish the feasibility of treating individual mice via therapeutic cloning. Derivation of 187 ntES cell lines from 24 parkinsonian mice, dopaminergic differentiation, and transplantation into individually matched host mice showed therapeutic efficacy and lack of immunological response.

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Available from: Sayaka Wakayama, Jun 09, 2015
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    • "Animal experiments All the animal experiments were performed according to the guidelines for the Care and Use of Laboratory Animals established by Beijing Association for Laboratory Animal Science. Unilateral PD mouse model was performed as previously described (Tabar et al., 2008): eight week old male C57BL/6 mice were used to establish PD models by 6-hydroxydopamine (6-OHDA, Sigma-Aldrich) administration. Mice were injected intraperitoneally (i.p.) with 25 mg/kg desipramine (Sigma-Aldrich) 20 min before anesthetization with ketamine and Xylazine (Sigma-Aldrich), followed by injection of 8 μg 6-OHDA in 2 μl saline into the right striatum (A/P 0.5 mm, M/L −2.3 mm, D/V − 3.2 mm). "
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    ABSTRACT: Lmx1a plays a central role in the specification of dopaminergic (DA) neurons, which potentially could be employed as a key factor for trans-differentiation to DA neurons. In our previous study, we have converted somatic cells directly into neural stem cell-like cells, namely induced neural stem cells (iNSCs), which further can be differentiated into subtypes of neurons and glia in vitro. In the present study, we continued to test whether these iNSCs have therapeutic effects when transplanted into a mouse model of Parkinson's disease (PD), especially when Lmx1a was introduced into these iNSCs under a Nestin enhancer. iNSCs that over-expressed Lmx1a (iNSC-Lmx1a) gave rise to an increased yield of dopaminergic neurons and secreted a higher level of dopamine in vitro. When transplanted into mouse models of PD, both groups of mice showed decreased ipsilateral rotations; yet mice that received iNSC-Lmx1a vs. iNSC-GFP exhibited better recovery. Although few iNSCs survived 11weeks after transplantation, the improved motor performance in iNSC-Lmx1a group did correlate with a greater tyrosine hydroxylase (TH) signal abundance in the lesioned area of striatum, suggesting that iNSCs may have worked through a non-autonomous manner to enhance the functions of remaining endogenous dopaminergic neurons in brain. Copyright © 2014. Published by Elsevier B.V.
    Full-text · Article · Oct 2014 · Stem Cell Research
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    • "). This observation, combined with the lack of immune rejection of isogenic cells following autologous transfer of oocyte-reprogrammed murine cells (Tabar et al., 2008), suggests the oocyte may possess unknown factors necessary to fully epigenetically reprogram somatic cell nuclei into an ES cell-like, immune-competent pluripotent state. I recently observed rhesus monkey SCNT- ESCs demonstrated greater transcriptional similarities with rhesus ESCs than do rhesus iPS cells (Byrne, 2011) suggesting the same underlying phenomenon of more complete reprogramming observed in the mouse appears to be the case for primate oocyte-based reprogramming. "
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    ABSTRACT: John Gurdon's discovery that somatic cells could be reprogrammed back into a pluripotent state has immense implications across multiple different fields, including the future potential for autologous cellular therapies. This review briefly examines the history of nuclear reprogramming, from Gurdon's original work in amphibia, through the generation of oocyte-reprogrammed pluripotent stem cells in the non-human primate and recent defined factor-based reprogramming approaches to generate human induced pluripotent stem (iPS) cells. This review also examines the five principle challenges towards safely advancing pluripotent stem cell derivatives into personalized human therapeutics, specifically: genetic stability, epigenetic memory, post-transplantation efficacy, post-transplantation safety and feasibility, and additionally discusses various hypotheses that may play a role in resolving the aforementioned challenges. Focused on iPS cells and derivatives, these hypotheses essentially deal with aging research, genomic stability and culture conditions, immunogenicity and epigenetic memory, epigenetic memory elimination by chromatin modifying chemicals or by developmental competence factors and/or by candidate oocyte reprogramming factors (CORFs), and small molecules acting on the blood-brain-barrier. In light of these hypotheses, progress in nuclear reprogramming mechanistic are discussed in terms of securing the therapeutic promise of autologous reprogrammed personalized stem cell derivatives in the foreseeable future, thereby opening a probable new era for anti-aging control and regenerative medicine.
    Preview · Article · Feb 2013 · Gene Therapy and Regulation
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    • "Analysis of this DA neuron production has not always distinguished among the many different classes of neurons that produce DA throughout the neuraxis, but recent advances have made possible the differentiation from pluripotent cell sources of regionally specific mid-brain DA neuronal subtypes whose deficiency is most affected in PD is possible, and such cells have been documented to function in rodent and primate models (Chambers et al., 2009; Fasano et al., 2010; Kriks et al., 2011). Moreover, techniques for producing personalized autologous stem cells via somatic cell reprogramming now exist, and it has been shown that autologous cells function better than cells derived from unrelated donors in rodent models of PD transplant (Tabar et al., 2008). The availability of highly specified, defined, autologous DA neuron preparations creates legitimate opportunities for testing in PD patients, including the testing of specific doses to establish a dose-response curve. "
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    ABSTRACT: Stem cells are the seeds of tissue repair and regeneration and a promising source for novel therapies. However, apart from hematopoietic stem cell (HSC) transplantation, essentially all other stem cell treatments remain experimental. High hopes have inspired numerous clinical trials, but it has been difficult to obtain unequivocal evidence for robust clinical benefit. In recent years, unproven therapies have been widely practiced outside the standard clinical trial network, threatening the cause of legitimate clinical investigation. Numerous challenges and technical barriers must be overcome before novel stem cell therapies can achieve meaningful clinical impact.
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