The Institute for Translational Neurosciences of Paris (IHU-A-ICM), carried by the Université Pierre et Marie Curie – Paris 6 (UPMC-P6), the Institut National de la Santé et de la Recherche Médicale (INSERM), the CHU Pitié-Salpêtrière (Public Assistance - Hospitals of Paris), the Centre National de la Recherche Scientifique (CNRS), the Institut du Cerveau et de la Moelle épinière (ICM) and the International Fund Raising for Alzheimer’s Disease Foundation (IFRAD), brings together a critical mass of research expertise (approximatively 500 researchers/clinicians, engineers/technicians, administrative and logistics agents, post-doctoral fellows and PhD students working for most of them at the Research Centre of the Institut du Cerveau et de la Moelle épinière (CRICM) directed by Bernard Zalc (AERES mark : A), training and care in the field of diseases of the nervous system to understand their mechanisms and develop tools for diagnosis, prevention and treatment of Parkinson's disease, Alzheimer, multiple sclerosis, epilepsy, etc. To transform research results into new processes and therapeutic tools, this project relies on the construction of infrastructure for translational research with a platform for imaging and electrophysiology, a data processing center and biostatistics, and two modeling centers (animal modeling, modeling cellular and screening drug candidates) and a center clinical trials (the “CIC” – see below). Wide open to industrial partnerships, this project will increase the visibility of France at international level in neuroscience (Total funding : ¤ 55 million).
On a scientific level, advances are expected in the understanding of the mechanisms of neuronal death in neurodegenerative diseases, predictive biomarkers and mechanisms of neuroprotection, but also in the understanding of the repair of nervous tissue, determinism and trigger seizures, and disorders of the brain mechanisms mood and motivation. Each issue is addressed through a disease model, then apply for other nervous system disorders.
With this ambitious project, the establishment of a research and care center, with a high and global visibility, and the establishment of an infrastructure for translational research in neurosciences combining imaging, electrophysiology, animal models, cellular models, clinical, research, biostatistics and data processing is clearly desired. It also reinforces excellence in care, and establishes a program of international and interdisciplinary training for scientists, engineers, professional care. It also includes training in project management and entrepreneurship. At last, it provides a strong policy of recruiting international researchers and research teams to enhance the skill of the site. The training involves several famous and recognized Masters and Doctoral schools and has a multidisciplinary dimension to develop innovative dual training courses
With this critical mass of expertise in research and care and this sector translational, multiple industrial partnerships will emerge on the site, which will also attract local, national or international translational research projects in order to effect the transfer of experimental results to the development of innovative products for the prevention, diagnosis and treatment in a considerable potential market.
The Clinical Investigation Centre (CIC) (AERES mark : A+) directed by J-C. Corvol is a research AP-HP/Inserm facility (hosted by the Institut du Cerveau et de la Moelle Epinière) providing administrative and logistic assistance to investigators in executing clinical research. During these past 2 years, the CIC has performed more than 50 studies representing around 3,000 visits for 500 patients. At the interface between researchers and clinicians, the CIC will promote translational research.
The IHU-A-ICM participates in the development and updating of several platforms and advanced technology core facilities that allow translational research in neurosciences, neurology and psychiatry to be developed. Several of them are hosted at the ICM Foundation.
These platforms consist in biological collection of DNA, cells and brain tissues of well characterized patients, cohorts of patients and biology oriented platforms and facilities. These platforms can support early validation of target or proof of concept. The NeurATRIS support should allow the increase of the candidate drugs and professionalize the translational research to clinical studies.
Brain Bank :
The Brain Bank was founded and is funded by a consortium of Patients' Association (France Alzheimer, France Parkinson, Research Association on Multiple Sclerosis, CSC = "Understanding cerebellar syndromes"), associated in an “Economic interest group” (GIE) to collect nervous system biological samples ("NeuroCEB"). The Bank is a national project involving 14 neuropathological centres in France; it has received housing facilities in the Pitié-Salpêtrière Hospital where the central unit is located; C. Duyckaerts (one of the CRICM’s team leaders) is its scientific administrator. It receives frozen samples from a network of neuropathology experts distributed over the metropolitan territory. The Bank has signed a general convention with all the 14 University Hospitals involved in the project. It promotes a Brain Donation program. The coordinator of the Bank receives donation consents. A scientific committee, specific to each sample collection (Alzheimer disease and related disorders, Parkinson Disease, Multiple Sclerosis, Ataxias) reviews the research project associated with the tissue request and makes them available to the researchers when appropriate. The Brain Bank has developed a Quality Management System and is certified (AFNOR NF S 96-900) since June 2010. It ensures the post mortem study of several cohorts of patients in AD (MultiMA Cohort, Bruno Dubois) and in ALS-Dementia (Laurence Caruelle, Caen Hospital). The Brain Bank has received 1850 consents and has collected 320 brains in a period of 6 years.
DNA and cell bank:
The DNA and cell bank-Cricm (directed by A. Brice) is a specialized biobanking structure devoted since 1990 to provide collections of biological resources from cohorts of patients for research in neurology and psychiatry. This platform supplies the technical expertise and logistics for the reception, preparation, storage and distribution of biological samples – mostly DNA extracts, lymphocytes, lymphoblast cell lines and, more recently, primary culture of fibroblasts and plasma– together with associated data. The bank is an internationally recognized structure which collaborates with numerous clinical and research networks. The collections for Parkinson’s Disease, spinocerebellar degenerations, Charcot-Marie Tooth disease, fronto-temporal dementia and epilepsy are, or are among, the most important ones worldwide. The bank currently manages 25 ongoing projects and 37 collections from over 25 different pathologies, representing 40 000 registered subjects and 140 000 stored samples (oct 2012). A LIMS (Laboratory Information Management System) is being implemented to administer all processes and stocks of biological samples, in interface with associated clinical and biological data. The platform is certified since 2009 for its management of quality insurance according to the national referential NF S96-900 for Biological Resource Centres (BRC), derived from the ISO 9001. This has structured its quality insurance and management of research projects, and allowed to keep pace with the increased regulation of biobanking activities. In this respect, the bank is an associated member to several projects aiming to define conditions of international harmonisation of practices and management of biobanks (The French Infrastructure BioBanques and the European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI)). It is also acknowledged as an IBiSA platform (French “Infrastructures en Biologie Santé et Agronomie”). The bank is ahead of a major evolution by being a component of an integrated BRC devoted to academic and industrial research in neurology and psychiatry, which will open in 2014.
BRC-REFGENSEP Platform :
The Biological Resources Center (BRC) of the French Multiple Sclerosis Genetics Group (REFGENSEP) aims to collect blood samples of MS patients and their family in order to constitute a large French cohort to perform consistent statistical analyses with pertinent clinical and molecular annotations. The BRC has been officially labelled by INSERM and legalized by Research Ministry in 2008 (N°DC-2008-539, AC-2008-548). The BRC is part of the national network of BRC (Biobanque) and of an european group, BBMRI (Biobanking and Biomolecular Resources Research infrastructure). The BRC is labeled as an IBiSA platform. Trough the French genetics MS group (REFGENSEP), a referent center network, patients are recruited from all over France in 23 clinical neurology departments specialized in MS. The BRC gathers lymphoblastoïde lineages, DNA samples and all clinical records. c A computer data bank has been developed to correlate each sample with clinical annotations such as age at onset, disease duration, MS form (relapsing remitting MS, primary or secondary progressive MS), the expanded disability score (EDSS), allowing to calculate the most accurate severity score designed for genetic studies of MS severity: the MSSS score. A quality management system has been set up in the BRC to provide the best service with homogenized process and to monitor the samples transfers. The NF S96-900 certification is planned for the end of 2012. The BRC manages to date 2447 clinically annotated patients and 2600 healthy controls. At the interface between scientific and clinical communities, the BRC is a resource of general interest which has been involved in national and international collaborations. 18.780 biological resources have been provided by the BRC since 2007 leading to 16 publications (mean impact factor of 10.3). In the next years the BRC plans to:
- Increase the collection up to 5,000 patients;
- Update clinical features, focusing on MS severity including MRI;
- Collect new information regarding treatment response;
- Build up a database that correlates genetic results with clinical data;
CNS tumour bank :
The “CNS tumour bank” (directed by J-Y Delattre) has been established in January 2000. It contains more than 5000 tumour samples and constitutes the largest European CNS tumour bank. The bank collects and stores in liquid nitrogen, tumours, blood, and more recently (2008) CSF and plasma samples from all patients with brain tumours undergoing surgery at the Pitié Salpêtrière Hospital. In addition, in anaplastic oligodendroglial tumours the tumour bank collects tumours from all academic centres countrywide (National Reference Centre POLA). Samples are processed according to the guidelines of the « Haute Autorité de Santé ». Several molecular biology techniques are used in routine to characterize the tissue stored in the tumour bank (e.g. microsatellites analysis, Single Nucleotide Polymorphism array, quantitative PCR, Sequencing, genomic and expression microarrays, immunohistochemistry, in-situ hybridation). The combined use of these tools by the laboratory members of Cricm’s experimental Neuro-Oncology team (directed by J-Y Delattre) constitutes the basis for translational research projects conducted on selected subpopulations defined by molecular, histological or clinical criteria.
Animal facility :
The ICM animal core facility (directed by P. Ravassard) presents a unique organization in Paris with 3000 m2 dedicated to the development of novel animal models for all main diseases affecting the central and peripheral nervous system (rodents, zebrafish and non-human primates) and their use in preclinical studies. Such facility plays a crucial role to reach the ICM Foundation’s ambition in translational neuroscience research. The projects already launched at the ICM involve models of Parkinson disease, Alzheimer disease, myelination diseases, amyotrophic lateral sclerosis, spinocerebellar ataxias, spastic paraplegia, Huntington disease, frontotemporal lobar degeneration, neuropsychiatric diseases and different forms of epilepsy. The platform contains three complementary sectors dedicated to zebrafish, rodents and non-human primates. In each sector, animal modelisation of human diseases is achieved by surgical, chemical (toxin-based) and/or transgenic approaches.
Vectoroly platform :
The overall goal of this platform (directed by P. Ravassard) is to provide the members of the ICM and its Research Centre with standardized and efficient tools to perform gene transfer experiments. Viral mediated gene transfer is a powerful tool for a large variety of in vivo and ex vivo experiments such as cell population tracing, gain and loss of function. It also represents the most efficient approach to generate transgenic animal models (from rodents to large animals). Importantly, gene transfer is the only efficient strategy available that allows genetic manipulation of primary cell cultures or tissue/organs from human origin. The platform has developed a standardized and robust method (Collombat et al. Cell 2009) to generate transgenic mice using lentiviral mediated gene transfer. Using such procedure the number of transgenic animals obtained is above 90% with an expression penetrance above 80%. In other words, more than 40 transgenic animals can be generated from one single injection session. Such high yields are compatible with screening purposes both for gain and loss of function experiments. Therefore any putative target can be validated in months by generating over expression and loss of function models.
Cell Culture core facility :
The ICM cell culture core facility (directed by P.P. Michel) aims (i) at ensuring complete and rapid access to researchers from the Institute, as well as from academic or industrial partners to a variety of cell culture models, cell biology protocols and sophisticated technological tools(inverted fluorescence microscopy workstations, infrared fluorescence imaging, flow cytometric analysis, microfluidic chambers,…) and (ii) at providing a scientific environment that favors contacts and creates a strong partnership between researchers. The establishment covers a total floor area of 2x 240 meter squares and contains 18 independent culture boxes, some of them being equipped for partners of the biotech incubator. Data management is under the supervision of senior researchers working on brain pathologies of neuronal (Alzheimer’ disease, Parkinson’ disease, Amyotrophic lateral sclerosis,…) or glial (multiple sclerosis, brain tumors)origin. An automated cell culture workstation will serve to perform medium throughput screening of compounds with potential therapeutic interest for brain or spinal cord pathologies. Both hypothesis driven and blind screening approaches will be developed.
Pitié-Salpêtrière Cell Imaging platform :
The platform (300 m2) (directed by A. Baron and C-M. Bachelet) is part of the Cell Imaging Network of UPMC and houses a panel of resources allowing to accomplish light microscopy (brightfield, confocal and multiphoton) and electron microscopy (TEM with tomography) to perform 3D imaging in vitro or in vivo. The goal of this platform which is located in the ICM Building is to provide the community with a set of large equipments and advanced technologies, to advise and assist researchers in the realization of their projects and keep them informed of new developments in bioimaging. Scientific projects are multiple and focus on the physiology, physiopathology and repair of the systems in 3 major fields of investigation : Heart-Muscle-Vessels (IFR14), Immunity, Cancer and Infection (IFR 113) and Neurosciences (CRICM). The acquired knowledge should also contribute to the development of strategies aiming at treating diseases affecting these systems.
Genotyping and sequencing platform :
This platform (directed by G. Stevanin) consists of five people: a scientific leader, an operations manager, an engineer responsible for the genotyping of animals and two technicians responsible for sequencing, real-time PCR and microarray technical. One of his goals is to provide a set of tools and services to reduce costs and increase data rates (miniaturization) by the use of innovative technologies. Then diagnostic tools and / or prognosis can be set up for their wider use in clinical practice. Thus the platform is based not only on innovative technologies, but also knowledge of structures and diagnostic industry partners. In the medium term, the platform wants to increase its activity in high-throughput real-time PCR and sequencing. This will be done by optimizing the procedures on real-time PCR machine 1536 wells, but also by the operation and implementation of protocols for capture and designate experiments on our high-throughput benchtop sequencer (50Mb). These processes include quality and quantification of products upstream of each technology. The idea is to better respond to user requests through productive and validated workflow.
Imaging platform (CENIR) :
CENIR is ICM and CRICM imaging platform. CENIR provides cutting edge neuroimaging and neurophysiology tools for neuroscience and clinical research projects. It aims at providing the best imaging tools and methodological expertise for researchers, clinicians, and biologists to answer neurobiological questions as well as the best technological expertise for methodologists to developed new image analysis and signal processing approaches. S. Lehericy, head of the CENIR, is in charge of coordinating the neuroimaging workpackage of the IHU project for translational neuroscience.
CENIR offers a large choice of tools, including MRI, PET, invasive and non invasive electrophysiology techniques such as MEG and EEG, TMS, 3-D stereotaxy for depth electrodes. CENIR benefits from its unique location in the Pitié-Salpêtrière hospital and ICM building, and also from the complementary expertise of ICM and CRICM research teams allowing efficient and synergistic interactions of methodology, image analysis, signal processing, neurobiology, neurophysiology, and clinical teams.