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Publications (5)24.69 Total impact

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    ABSTRACT: Decreased expression of neuronal genes such as brain-derived neurotrophic factor (BDNF) is associated with several neurological disorders. One molecular mechanism associated with Huntington disease (HD) is a discrete increase in the nuclear activity of the transcriptional repressor REST/NRSF binding to repressor element-1 (RE1) sequences. High-throughput screening of a library of 6,984 compounds with luciferase-assay measuring REST activity in neural derivatives of human embryonic stem cells led to identify two benzoimidazole-5-carboxamide derivatives that inhibited REST silencing in a RE1-dependent manner. The most potent compound, X5050, targeted REST degradation, but neither REST expression, RNA splicing nor binding to RE1 sequence. Differential transcriptomic analysis revealed the upregulation of neuronal genes targeted by REST in wild type neural cells treated with X5050. This activity was confirmed in neural cells produced from human induced pluripotent stem cells derived from a HD patient. Acute intra-ventricular delivery of X5050 increased the expressions of BDNF and several other REST-regulated genes in the prefrontal cortex of mice with quinolinate-induced striatal lesions. The present study demonstrates that the use of pluripotent stem cell derivatives can represent a crucial step toward the identification of pharmacological compounds with therapeutic potential in neurological affections involving decreased expression of neuronal genes associated to increased REST activity, such as Huntington disease.
    Full-text · Article · Sep 2013 · Stem Cells
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    ABSTRACT: Wnt-ligands are among key morphogens that mediate patterning of the anterior territories of the developing brain in mammals. We qualified the role of Wnt-signals in regional specification and sub-regional organization of the human telencephalon using human pluripotent stem cells (hPSCs). One step neural conversion of hPSCs using SMAD inhibitors leads to progenitors with a default rostral identity. It provides an ideal biological substrate for investigating the role of Wnt signaling in both antero-posterior and dorso-ventral processes. Challenging hPSC-neural derivatives with Wnt-antagonists, alone or combined with sonic hedgehog (Shh) we found that Wnt-inhibition promote both telencephalic specification and ventral patterning of telencephalic neural precursors in a dose-dependent manner. Using optimal Wnt-antagonist and Shh-agonist signals we produced human ventral-telencephalic precursors, committed to differentiation into striatal projection neurons both in vitro and in vivo after homotypic transplantation in quinolinate-lesioned rats. This study indicates that sequentially organized Wnt-signals play a key role in the development of human ventral telencephalic territories from which the striatum arise. In addition, the optimized production of hPSC-derived striatal cells described here, offers a relevant biological resource for exploring and curing Huntington disease.
    No preview · Article · Sep 2013 · Stem Cells
  • Pedro Viegas · Camille Nicoleau · Anselme L Perrier
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    ABSTRACT: Huntington's disease cell therapy is for the moment the only therapeutic approach for this devastating neurodegenerative disorder that has demonstrated significant and long-lasting functional benefits in patient. Logistical and biological difficulties associated with the use of human fetal tissue however dramatically reduce the number of patients eligible to this therapy. During the past decade, the exploration of alternative cellular sources, conducted in parallel to the clinical trials, has gradually put forward human pluripotent stem cells as prime candidate for Huntington's disease cell therapy. Protocols for the differentiation of such cells into therapeutically relevant striatal neuron precursors require thorough understanding of the molecular determinant that controls the development of the anterior and ventral part of the forebrain from which the striatum arises. Key secreted molecules that play pivotal roles in the development of these regions in mice have been successfully used to direct the specification of neural derivatives of human pluripotent stem cells. Assessment of the therapeutic potential of resulting striatal grafts has made significant progress in the last 4 years. The proof of principle that human embryonic stem cell derivatives can achieve some degrees of functional striatal repair in a mouse model of Huntington's disease is now established. As in other neurodegenerative diseases such as Parkinson's disease, recent developments have raised hopes for stem cell-based therapy of Huntington's disease.
    No preview · Article · Nov 2012 · Progress in brain research

  • No preview · Conference Paper · Oct 2012
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    Camille Nicoleau · Pedro Viegas · Marc Peschanski · Anselme L Perrier
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    ABSTRACT: Intra-striatal transplantation of homotypic fetal tissue at the time of peak striatal neurogenesis can provide some functional benefit to patients suffering from Huntington's disease. Currently, the only approach shown to slow down the course of this condition is replacement of the neurons primarily targeted in this disorder, although it has been transient and has only worked with a limited number of patients. Otherwise, this dominantly inherited neurodegenerative disease inevitably results in the progressive decline of motricity, cognition, and behavior, and leads to death within 15 to 20 years of onset. However, fetal neural cell therapy of Huntington's disease, as with a similar approach in Parkinson's disease, is marred with both technical and biological hurdles related to the source of grafting material. This heavily restricts the number of patients who can be treated. A substitute cell source is therefore needed, but must perform at least as well as fetal neural graft in terms of brain recovery and reconstruction, while overcoming its major obstacles. Human pluripotent stem cells (embryonic in origin or induced from adult cells through genetic reprogramming) have the potential to meet those challenges. In this review, the therapeutic potential in view of 4 major issues is identified during fetal cell therapy clinical trials: 1) logistics of graft procurement, 2) quality control of the cell preparation, 3) immunogenicity of the graft, and 4) safety of the procedure.
    Full-text · Article · Oct 2011 · Journal of the American Society for Experimental NeuroTherapeutics