Gribaudo et al. Stem Cell Reports 2019
Postdoctoral Fellow position in Neurodegenerative diseases group:
The Neurodegenerative disease group is looking for a talented Postdoctoral Fellow to conduct research on experimental Huntington disease cell therapy in rodents. Research will involve the transplantation of different 3D striatal organoids derived from human pluripotent stem cells. The trainee will gain experience in state-of-the-art pluripotent stem cell technology and animal model experimentation at I-Stem and in collaborator lab (CEA-MIRCen, Fontenay-aux-Roses where all animal experiment shall be conducted.
Minimum Education and Skills Required for Consideration:
- A Ph.D. degree in life or biomedical sciences, or a related discipline is required.
Preferred Education and Skills:
- Experience in in animal experimentation (rodent), tissue cultures (neuronal cell biology), cell therapy
Funding: ANR “PARKINGTON” 24 months Postdoc position,
Neurodegenerative diseases group:
Team: (last updated October 2018)
Anselme L. Perrier : Research Director DR2 (Inserm U861, Group Leader)
Morgane Louessard: Post-doc (Inserm – JPND « ModelpolyQ »)
Patricia Lino: Engineer (Inserm – ANR)
Julie Bigarreau: PhD Student UEVE (Inserm – ANR/ Labex « Revive »)
Juliette Duchesne de Lamotte: PhD Student UEVE (Inserm CIFRE IPSEN)
Aims and background:
The group’s objectives are focused on using neural progenies of human Pluripotent Stem (hPS) cells to 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.
Bench-to-bedside cell therapy program for HD
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.
This translational cell therapy program is conducted within a European consortium (FP7 Repair-HD: http://www.repair-hd.eu). The rational is to use hPSCs as potent sources of cells to produce cell therapy product (CTP) for HD patient. We focus more specifically on: (A) GMP translations of CTP production and Quality Control assay development to evaluate such production (in collaboration with Roslin Cells, UK). (B) Pre-clinical in vivo functional testing in rodent and non-human primate models of HD (in collaboration with Dr. Hantraye & Dr R Aron-Badin CEA-MIRCen and Dr. Dunnett, Cardiff University, UK). (C) Immunogenicity of PSC-derived CTP: recipient response to allogeneic CTP in non-human primate models of HD (in collaboration with Dr Hantraye/Aron-Badin and Pr E Cozzi, Padova, Italy)
Disease modelling with disease or patient-specific hPSC
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 hPSC (embryonic or induced) 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.
Our current objectives is to find new insights in both cell autonomous and non-cell autonomous pathological cascades in HD. The rational is to make the most of the key properties of disease-specific hPSCs as versatile and highly relevant tools and biological substrates to study HD. We develop protocols, vector and lines to challenge HD genetic determinant in selected relevant cell populations (cortical or striatal neurons, astrocytes) alone or integrated within in vitro neuronal network in microfluidic chambers. Next we these tools to explore how mutations in the HTT protein impact on human cortical development and human neuronal and astroglial functions. Finally we aim at identifying phenotype specific transcriptional targets of mutant HTT (mut-HTT) or HTT loss of function in relevant neuronal/glial populations.
Drug discovery for HD with hPSC
Our general aim is to identify therapeutically relevant signaling pathways and lead-compound(s) for HD. We more precisely develop molecular and phenotypic screening assays to report HD-mediated functional impairments in HD-hPSC neuronal or glial. Next we use such assays to identify LEAD chemical compound(s) with therapeutic potential for HD or to validate drug or gene-based therapeutic approaches developed by our collaborators (Pr. Nicole Deglon, CHUV, Laussanne Swiss) or industrial partners.
BENCHOUA, Alexandra; (FR). PERRIER, Anselme; (FR). AUBRY, Laetitia; (FR).
Method and medium for neural differentiation of pluripotent cells
MIRCEN – CEA (Fontenay-aux-Roses) – CEA CNRS UMR9199
Dr. Philippe Hantraye & Dr. Romina ARON-BADIN (FP7-Repair-HD)
Dr. Emmanuel Brouillet
CNRS UMR7102, UPMC Paris
Dr. Jean-Michel Peyrin (ERANet Neuron Microdeg)
CNRS UMR9197, Gif-sur-Yvette, France
Dr. Ronald Melki
CHUV, LABORATOIRE DES NEUROTHÉRAPIES CELLULAIRES ET MOLÉCULAIRES, Lausanne, (Swiss)
Dr. Nicole Deglon
Cardiff University, School of Biosciences
Steve Dunnett et Meng Li (FP7-Repair-HD)
Roslin Cells Therapy, Edinburgh, UK
Brain Repair and Imaging in Neural Systems, Lund University, Sweden
Dr. Deniz Kirk