Neurodegenerative diseases
Team :
Anselme Perrier : Research Associate CR2 (INSERM)
Camille Nicoleau: Post-doctoral Fellow
Maxime Feyeux : PhD Student
Aurore Bugi : Qualified research technician (CECS)
Véronique Cordette: TE (INSERM)
Aurore Bugi : Qualified research technician (CECS)
Véronique Cordette: TE (INSERM)
Jérémie Charbord : PhD Student
Pedro Viegas : Post-doctoral Fellow
Huntington disease (HD) is a progressive autosomal dominant disorder characterized by motor, cognitive, and psychiatric/behavioural disturbances. It belongs to a family of diseases caused by mutations that expand a CAG repeat tract, leading to long stretches of polyglutamine (polyQ) in the encoded protein (huntingtin (Htt), encoded by the HD/IT15 gene). The prevalence of HD, about 3 per 10,000 in populations of western European descent, is by far the highest of all known monogenic disease affecting the brain. The neuropathological features of HD typically include neuronal degeneration especially severe in the striatum, with specific targeting of medium-spiny GABA-ergic neurons (MSN). As striatal degeneration progresses, degenerative changes occur to other brain regions connected to the striatum, in particular the neocortex. There is presently no way to stop or reverse the course of HD. Most of the patient with HD dies within 15-18 years of the onset.
Huntington’s disease (HD) is partially amenable to treatment by substitutive cell therapy. However, this technique is marred by logistic problems that restrict considerably the number of patients who may benefit from it. Potent alternative source of cells is therefore acutely needed. Due to their original properties, hESC are prime candidate which relevance have already been demonstrated for cell therapy of Parkinson’s disease. Even though it may correct existing neuronal losses, cell replacement is not by itself a cure for HD as it cannot stop the progression of the neurodegeneration in the patient’s brain. In addition to substitutive therapy, efficient neuroprotective treatments should, therefore, be implemented. The search for such a complementary treatment is a major endeavour. Despite the wealth of existing cellular model, this undertaking probably require additional cellular model of HD more closely replicating the patient’s situation. We postulate that HD mutant hESC lines can constitute such model and would be key to the exploration of the molecular mechanisms of the disease and ultimately allow the screening of therapeutic compounds endowed with a therapeutic potential. Determining the potential of hESC progenies for HD treatments depend on our capacity to control their quality (pluripotence, genetic alteration …) and to generate hESC-derived population that are both relevant and convenient. This initial task includes in particular the capacity to generate from hESC, striatal neurons progenitors amenable to grafting and large quantity of easy-to-use, homogenous, self-renewable and multipotent (neurogenic) neural stem cells population either by conventional methods or via bioreactor culture system. Within the general framework described above about the use of hESC (normal or mutant) to ultimately develop complementary treatments for patients suffering from HD, The main objectives of the “neurodegenerative diseases group” are):
A – Substitutive cell Therapy: Production and assessment of the use of progenitors of GABA-ergic striatal neurons derived from normal hESC as grafting material for Huntington’s disease cell therapy. Development of a “safety switch” to ensure the safety of hES-derived graft for cell therapy. Development of the protocol for the production of clinical-grade striatal graft and of the methods for banking these grafts.
B – Pathological modelling and drug discovery: Development of a new human cellular model of HD, based on neural cells derived from hESC carrying HD mutation, for the exploration of molecular and cellular mechanisms of HD. Use neural, striatal or neuronal relevant progenies derived from HD-hESC as substrate for high throughput screening of potentially neurprotective compound.
Huntington’s disease (HD) is partially amenable to treatment by substitutive cell therapy. However, this technique is marred by logistic problems that restrict considerably the number of patients who may benefit from it. Potent alternative source of cells is therefore acutely needed. Due to their original properties, hESC are prime candidate which relevance have already been demonstrated for cell therapy of Parkinson’s disease. Even though it may correct existing neuronal losses, cell replacement is not by itself a cure for HD as it cannot stop the progression of the neurodegeneration in the patient’s brain. In addition to substitutive therapy, efficient neuroprotective treatments should, therefore, be implemented. The search for such a complementary treatment is a major endeavour. Despite the wealth of existing cellular model, this undertaking probably require additional cellular model of HD more closely replicating the patient’s situation. We postulate that HD mutant hESC lines can constitute such model and would be key to the exploration of the molecular mechanisms of the disease and ultimately allow the screening of therapeutic compounds endowed with a therapeutic potential. Determining the potential of hESC progenies for HD treatments depend on our capacity to control their quality (pluripotence, genetic alteration …) and to generate hESC-derived population that are both relevant and convenient. This initial task includes in particular the capacity to generate from hESC, striatal neurons progenitors amenable to grafting and large quantity of easy-to-use, homogenous, self-renewable and multipotent (neurogenic) neural stem cells population either by conventional methods or via bioreactor culture system. Within the general framework described above about the use of hESC (normal or mutant) to ultimately develop complementary treatments for patients suffering from HD, The main objectives of the “neurodegenerative diseases group” are):
A – Substitutive cell Therapy: Production and assessment of the use of progenitors of GABA-ergic striatal neurons derived from normal hESC as grafting material for Huntington’s disease cell therapy. Development of a “safety switch” to ensure the safety of hES-derived graft for cell therapy. Development of the protocol for the production of clinical-grade striatal graft and of the methods for banking these grafts.
B – Pathological modelling and drug discovery: Development of a new human cellular model of HD, based on neural cells derived from hESC carrying HD mutation, for the exploration of molecular and cellular mechanisms of HD. Use neural, striatal or neuronal relevant progenies derived from HD-hESC as substrate for high throughput screening of potentially neurprotective compound.
A) Experimental HD cell therapy:
The common risk to all forms of cell therapy is that grafted cells turn against the host, as it happened during our transplantation experiments of hESC-progenies in rats. Our goal is to develop a safety system based upon genetic engineering of the grafted cells, providing a mean to eliminate transplanted cells selectively in vivo, at will and at any time.
B) HD Pathological modeling and drug discovery:
Pathological modelling - Towards new insights in pathological mechanisms and the identification of new cellular markers of HD: Our first objective is to secure and bank mutant human pluripotent stem cells derived from PGD-tested embryos (HD-hESC) or patient somatic cells (HD-iPS). In order to explore HD pathological mechanism we aim at finding new cellular marker of the disease. A first approach of the group is to perform genome-wide differential transcriptomic analyses of HD vs. wild-type pluripotent stem cells and their relevant progenies. The immediate goal is to identify genes whose expression is modulated by the presence of the Huntington mutation.
Neuroprotection – Towards drug discovery to limit the extent and progression of neural cell loss: Our goal is to conduct high throughput screening of small molecules targeting HD cellular markers either already characterized (REST etc…) or identified by us. The identification of active small molecules with HTS may reveal unknown intracellular pathogenic mechanisms that will provide us with candidates for deriving original neuroprotective tools. The relevance of identified targets will be confirmed by activating/inactivating the corresponding pathways in cellular models.
Recent publication of the Neurodegenerative diseases group:
Human embryonic stem cells reveal recurrent genomic instability at 20q11.21.
Lefort N, Feyeux M, Bas C, Féraud O, Bennaceur-Griscelli A, Tachdjian G, Peschanski M, Perrier AL.
Nat Biotechnol. 2008 Nov 23. [Epub ahead of print]
Striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in quinolinic acid-lesioned rats.
Aubry L, Bugi A, Lefort N, Rousseau F, Peschanski M, Perrier AL.
Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16707-12. Epub 2008 Oct 15.
Improvement of Culture Conditions of Human Embryoid Bodies Using a Controlled Perfused and Dialyzed Bioreactor System.
Come J, Nissan X, Aubry L, Tournois J, Girard M, Perrier AL, Peschanski M, Cailleret M.
Tissue Eng Part C Methods. 2008 Aug 18. [Epub ahead of print]
Evolutionary forces shape the human RFPL1,2,3 genes toward a role in neocortex development.
Bonnefont J, Nikolaev SI, Perrier AL, Guo S, Cartier L, Sorce S, Laforge T, Aubry L, Khaitovich P, Peschanski M, Antonarakis SE, Krause KH.
Am J Hum Genet. 2008 Aug;83(2):208-18. Epub 2008 Jul 24.
