Neurodegenerative diseases
Team :
Anselme Perrier : Research Associate CR2 (INSERM)
Camille Nicoleau: Post-doctoral Fellow
Aurore Bugi : Qualified research technician (CECS)
Véronique Cordette: TE (INSERM)
Véronique Cordette: TE (INSERM)
Jérémie Charbord : PhD Student
Pedro Viegas : Post-doctoral Fellow
Sophie Aubert : Associate engineer (CECS)
Caroline Bonnefond : (CECS)
Aims and background :
The group’s objectives are focused on using neural progenies of human Pluripotent Stem (hPS) cells to better understand and develop new treatments for Huntington Disease (HD). This devastating neurodegenerative disorder belongs to a family of genetic diseases caused by mutations that expand a coding CAG repeat tract. The mean age of onset is 35, around 6,000 people are affected in France. No disease modifying therapies are available; HD therefore follows a slow progressive evolution leading to death within 15 years of onset of first symptoms. The team is conducting two major research programs dedicated to cell therapy on one hand and to pathological modeling and drug screening on the other hand.
HD therapy: stem cell-based cell replacement approach
Monkey embryonic stem cell derived striatal progenitors (A) and neurons (B) differentiated in vitro or in vivo (4 months pots-transplantation) in lesioned striatum of nude rat (C)
Strategy, means and methods :
Cell therapy
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. A potent alternative source of cells is therefore acutely needed. Due to their original properties, hPS cells are prime candidates whose relevance has already been demonstrated for cell therapy of Parkinson’s disease. Our long term goal is to promote the clinical application of such cells for HD. A critical step towards this goal is to demonstrate in pre-clinical conditions that the derivation of striatal neurons from hPS cells produces both functional and safe grafts in vivo.
Pathological modelling and drug screening
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 a wealth of existing cellular models, this undertaking probably requires additional cellular models of HD more closely replicating the patient’s situation. We postulate that HD mutant hPS (embryonic or induced) cell lines can constitute such models 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.
Results and future prospects :
Cell therapy
We have made progress in developing protocols that can generate transplantable and potentially functional striatal neurons from both human and monkey embryonic stem cells and tested them in model of HD rats and more recently of HD monkeys (allograft conditions). Many more challenges still lie ahead including: 1) further enhancement of differentiation protocols (at clinical grade standard); 2) functional assessment in HD monkeys; 3) management of safety issues (graft overgrowth).
We have made progress in developing protocols that can generate transplantable and potentially functional striatal neurons from both human and monkey embryonic stem cells and tested them in model of HD rats and more recently of HD monkeys (allograft conditions). Many more challenges still lie ahead including: 1) further enhancement of differentiation protocols (at clinical grade standard); 2) functional assessment in HD monkeys; 3) management of safety issues (graft overgrowth).
Pathological modelling and drug screening
One example of our progress is the screening of a library of 7000 chemical compounds to find drug modulating REST activity, a transcriptional regulator impaired in HD. With the High Throughpout Screening group, we have identified two chemical series with specific activity on REST in hPS cells-derived neural cells.
Primary screening steps, REST-activity assay on neural stem cells derived from hES cells
Publications :
Lefort N et al., Human embryonic stem cells and genomic instability. Regen Med. 2009 Nov;4(6):899-909. Review. Lefort N et al., A recurrent hotspot of genomic instability identified in human ES cells. Med Sci. 2009 Jan;25(1):99-101. Aubry L et al., Human embryonic stem cell derived striatal graft for Huntington’s disease cell therapy. Med Sci. 2009 Apr;25(4):333-5. Lefort N et al., Embryonic stem cells reveal recurrent genomic instability at 20q11.21 in the human. Nature Biotechnology 2008 Dec;26(12):1364-6 Aubry L et al., Striatal progenitors derived from human ES cells mature into DARPP-32 neurons in vitro and in quinolinic acid-lesioned rats. Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16707-12. Epub 2008 Oct 15.
Patent :
WO/2010/063848 (2010-06-10)
BENCHOUA, Alexandra; (FR). PERRIER, Anselme; (FR). AUBRY, Laetitia; (FR).
Method and medium for neural differentiation of pluripotent cells
Collaborations :
Dr. Philippe Hantraye and Dr. Nicole Deglon, MIRCEN, CEA, Fontenay-aux-Roses, France, (Pathological modelling of Huntington’s disease in HD human pluripotent stem cells progenies)
Dr. Frédéric Saudou and Dr. Sandrine Humbert, Institut Curie, CNRS UMR 3306, Inserm U1005, Orsay, France, (Pathological modelling of Huntington’s disease in HD human pluripotent stem cells progenies)
Dr. Nick Allen, Cardiff University, School of Biosciences, Cardiff, UK, (Pathological modelling of Huntington’s disease in HD human pluripotent stem cells progenies)
Dr. Lorenz Studer and Dr. Mark Tomishima, Sloan Kettering Institute, New York, NY, USA, (Stem cell therapy in a animal model of Huntington’s disease. (FP7-Neurostemcell)
Dr. David Sourdive, Cellectis, Romainville, France, (Stem cell therapy in a animal model of Huntington’s disease. (FP7-Neurostemcell)
Dr. David Klatzmann, Dr. François Lemoine and Dr Cohen, Service de Biothérapies, CNRS UMR7087, Hôpital de la Pitié-Salpêtrière, Paris, France, (Management of graft overgrowth for stem cell therapy of Huntington’s disease.(ANR TK-SAFE))
Dr. David Klatzmann, Dr. François Lemoine and Dr. Cohen, LTKfarma, Evry, France, (Management of graft overgrowth for stem cell therapy of Huntington’s disease.(ANR TK-SAFE))
Dr. Frédéric Saudou and Dr. Sandrine Humbert, Institut Curie, CNRS UMR 3306, Inserm U1005, Orsay, France, (Pathological modelling of Huntington’s disease in HD human pluripotent stem cells progenies)
Dr. Nick Allen, Cardiff University, School of Biosciences, Cardiff, UK, (Pathological modelling of Huntington’s disease in HD human pluripotent stem cells progenies)
Dr. Lorenz Studer and Dr. Mark Tomishima, Sloan Kettering Institute, New York, NY, USA, (Stem cell therapy in a animal model of Huntington’s disease. (FP7-Neurostemcell)
Dr. David Sourdive, Cellectis, Romainville, France, (Stem cell therapy in a animal model of Huntington’s disease. (FP7-Neurostemcell)
Dr. David Klatzmann, Dr. François Lemoine and Dr Cohen, Service de Biothérapies, CNRS UMR7087, Hôpital de la Pitié-Salpêtrière, Paris, France, (Management of graft overgrowth for stem cell therapy of Huntington’s disease.(ANR TK-SAFE))
Dr. David Klatzmann, Dr. François Lemoine and Dr. Cohen, LTKfarma, Evry, France, (Management of graft overgrowth for stem cell therapy of Huntington’s disease.(ANR TK-SAFE))
