European networks

Programs supported by the European Commission

Several teams of I-Stem are implied in programs supported by the European Commission within the framework ot the 7th outline program, one of which is coordinated by Marc Peschanski (SCR&TOX).

SCR&TOX

« Stem Cells for Relevant Efficient Extended and Normalized Toxicology »

Network coordinator : Marc Peschanski

Program summary:

The need for a profound shift in the way toxicology testing is carried out for chemicals in the pharmaceutical and cosmetic industry is clearly acknowledged by all, in the industry and academia as well as in institutional bodies. Change is inevitable because the current system is not based on fundamentally sound science, but rather on descriptive data from high dose animal tests. The extrapolations —across species, from high test doses to low exposures, and from descriptive endpoints in animals to their possible human correlates— are handicapped by the lack of underlying mechanistic information. Although this has been often instrumental in the past, it has also shown sometimes clearly unreliable. In addition, our current approach is too expensive and too slow,capable of only limited throughput (Kramer et el., 2007).

A number of expert reports and publications now call for re-orienting testing to the molecular level, highlighting the concept of “toxicity pathways” within human cells that would be triggered by a toxicant exposure at a low dose that by itself does not provoke major cell toxicity but induces changes in cell homeostasis to cope with the phenomenon (National Research Council of the US National Academies report, 2007; CIRM workshop report, 2008; Hartung, 2009). Repetition of exposure, or else increase in dosage may eventually lead to actual irreversible changes and severe consequences. Evaluation of toxicants calls, therefore, for new models to be created that will allow assessing toxicity pathway responses in vitro, that will deliver a more accurate profile of acute toxicity in humans and possibly also reveal more subtle chronic toxic contraindications. Implementation of this new strategy based upon in vitro tests requires the most relevant and reliable model systems, which should also be robust and scalable in order to be instrumental at an industrial scale.

This is at the core of the entire FP7 call for Alternative Testing, of which we address with the ScreenTox consortium the first line on “human-based target cells in vitro”. In response to the details of the call we have assembled a well-articulated group of partners with complementary expertise in order to evaluate the value of human pluripotent stem cell lines for elaborating assays of toxicity pathways that meet all challenges of the new strategy, from the most basic issues on mechanisms of differentiation up to the demonstration of normalized assays on industrial-scale platforms and validation. A particularly innovative aspect of our program is the emphasis on the full use and mastering of all the DIVERSITY and VERSATILITY offered by those cell lines, for analysis of multiple cell phenotypes (in 5 different organs of interest for toxicology), multiple conditions of exposure (single vs. repeated –low vs. high doses), multiple genotypes (offering a stochastic approach of human polymorphism in vitro) and multiple approaches (both in terms of analyses, in particular with “functional ‘omics”, and engineering to optimize and standardise) and most importantly newest cell biological approaches and molecular biological techniques will be undertaken for the successful cellular differentiation therapy leading to target cells relevant for assessing systemic repeated dose toxicity

The aim of the ScreenTox program, fully integrated with the other consortia selected for the entire call that will each bring expert bases for different aspects of the new strategy, is to PROVIDE biological and technological resources needed to assay toxicity pathways in vitro and to DEMONSTRATE on industrial platforms that these resources can be reliably and robustly implemented at the required scale.

The scientific objectives are:

  • To obtain the pluripotent stem cell lines required for the program both in terms of quality, i.e. ES and iPS from a sufficient number of donors, and quantity through implementation of scalable production technologies;
  • To design and implement optimal protocols for differentiation of pluripotent stem cells along 5 different lineages (liver, heart, CNS, epidermis and muscle), to fully terminally differentiated cells. For manufacturing and specific assay development reasons, some of the cell types, i.e. CNS, epidermis and muscle will be characterized in an additional stage, an intermediate precursor stage;
  • To design and implement engineering and production methods to optimize those differentiated cells specifically for toxicity pathways assays;
  • To identify and optimize, or otherwise develop and standardise technologies for exploring cell functions relevant to toxicity pathways assays;
  • To implement on the bench cell-based assays of toxicity pathways identified by the other consortia of the call using optimized and newly developed technologies;
  • To promote biological resources to scale, reliability and robustness for implementation on industrial HTS platforms;
  • To develop at least one stem cell-based assay of a toxicity pathway validated on the bench for implementation on industrial HTS platforms;
  • To demonstrate the value of at least one prototype of a stem cell-based toxicity pathway assay on industrial HTS platforms;
  • To enter at least one prototype of a stem cell-based assay of a toxicity pathway into normalization and validation;
  • To address the potential phenotypic diversity of cell lines and select a robust panel of cells for large scale preparation of test cultures that are suitable for high throughput screening.

Partnerships:

 

 

NEUROSTEMCELL

 

Program summary:

NeuroStemcell is formed to create a world-leading consortium that can take stem cell based therapies for Parkinson´s disease (PD) and Huntington´s disease (HD) to the clinic. The consortium brings 13 together elite European research teams and 3 SMEs from 6 EU member countries representing the broad range of expertise necessary to reach this goal, including stem cell specialists, developmental neurobiologists, scientists and clinicians with expertise in animal models of PD and HD and in vivo imaging, with the goal to develop safe and validated cells and clinical grade reagents to be used in clinical trials and eventually also in drug discovery. The regulatory, ethical and societal issues associated with the use of stem cells for therapy will be carefully considered as science progresses from bench to bedside.

PD and HD are ideal candidate diseases for restorative stem cell-based therapies. In both diseases the pathology is slowly progressive and characterized by the preferential loss of one type of neuron, i.e., the mesencephalic dopamine (mesDA) neurons in PD and the GABAergic medium sized spiny neurons in HD. The cell replacement strategy aims at substituting the lost mesDA and GABA neurons, respectively, by implantation of new functional cells. Although other cell types are ultimately affected, experimental evidence obtained in rodent and primate models of PD and HD, as well as the experience gained from clinical trials using grafts of fetal mesDA and striatal GABAergic progenitors, indicate that effective restorative therapies may be possible to achieve by neural transplantation in these two diseases. Further development of this approach, however, will critically depend on the development of alternative sources of therapeutically effective cells derived from stem cells.

NeuroStemcell is focused on the identification and systematic comparison of progenitor cell lines with the most favourable characteristics for mesDA and striatal GABAergic neuronal differentiation, generated either directly from human embryonic stem (ES) cells, from Neural Stem (NS) cells derived from ES cells or fetal brain, from induced Pluripotent Stem (iPS) cells or from in vitro short-term expanded neural progenitors from ventral midbrain grown as neurospheres (VMN, Ventral Midbrain Neurospheres)4, and perform rigorous and systematic testing of the most prominent candidate cells in appropriate animals models. The consortium will engage in parallel into a number of educational activities and promote the development of resources for patient groups, regulators and lay public.

Partnerships:

  •  EU hESC registry, European human embryonic stem cell registry

Coordinator: Anna Veiga (Barcelone )

Proposal abstract

Human embryonic stem cell (hESC) research holds promise for the development of therapies for degenerative pathologies, offers a tool for drug discovery and toxicity tests, for studying human development, disease physiology and gene control. hESC lines are currently derived in an increasing number of laboratories in Europe and around the world. A detailed registry of available cell lines will promote the validation and efficient use of these precious cells for research and application. Comparable information is needed about the origin of the cell lines, the methodology and standards for their derivation and the characteristics to assess their availability for research and future therapies. The growing use of hESC by the scientific community demands a high quality and comprehensive registry. The aim of the proposed European hESC registry is to promote access to all hESC lines derived in Europe and transparency about their characteristics. Only well defined and adequately characterised hESC lines according to the parameters established by the registry be listed. To determine listing decisions, the features of the cell lines will be evaluated according to defined scientific and quality standards. Data such as the origin, the derivation methodology, as well as the different parameters used for characterisation will be recorded for each hESC line in the registry. Contact data and legal status will also be available for each cell line. Each cell line will be annotated with essential and useful information on their characteristics and applications. The registry will contribute to the harmonization of the use of the reported cell lines, spreading of standards and good practice in cooperation with other international registries. It will contribute to the responsible limitation of the number of embryos needed for derivation of new cell lines by promoting access to existing hESC lines, exchange of information about these cells and transparency towards the European legislative landscape. Registry of the database and website will facilitate the continuous mapping of the research and legislative landscapes in a topographical online design. The registry will also serve as a communication and consultation platform for hESC researchers, clinical groups, patients groups and the public at large for information on hESC. A Steering Committee (StC) of national representatives with inventory and administrative tasks will be formed. One representative from each country where hESC research is performed will serve as national contact person. Updated information about the situation in each country and the cell lines that are available will be provided by the StC. A Scientific Advisory Board (SAB) is constituted of leading European scientists in the field of hESC research. The SAB will advise and assure the scientific and technical quality of the registry and serve as control body of the registry. The operational management will be coordinated by a Berlin-based information technology (IT) team and a Barcelona-based operational team, which will determine and control hESC-eligibility criteria and coordinate work with the StC and the SAB. The selection of partners will guarantee the short-term establishment of an independently managed European registry of outstanding quality, close interaction with relevant European and global initiatives, international acceptance and global leadership.

 

  •   Myelin orphan diseases in health-MYELINET

Coordinator: Odile Bosepflug-Tanguy (Clermont-Ferrand)

The objective of the Action is to better understand and fight diseases affecting the CNS nerveinsulating myelin such as inherited leukodystrophies and white matter diseases of the premature. These pathologies are widely studied around Europe. Given the rarity of specific diseases, however, the critical mass to generate scientifically exploitable data is lacking. Therefore this action will combine a number of recognized European research groups for a coordinated approach to fight these diseases. Four working groups will be created: WG1 Functional biology and genomics / post-genomics analysis; WG2-Structural biology, proteomics and NMR analysis for the development of diagnostic tools and drug design; WG3-Prevention and new therapeutic options; WG4-Information and communication. MYELINET will promote medical, scientific and technical exchange by the creation of a common database; develop teaching, training and exchange programs for students; organise meetings and workshops; debate ethical and societal implications and concerns ofresearch issues; communicate with the public and inform affected families; and interact with experts of related diseases such as multiple sclerosis. A yearly international congress coupled to a more general public information day will be organised. This will pave the way for a more ambitious Consortium to prepare a European FP7 project.

 

  •   European Network for the Advancement of Clinical Gene Transfer and Therapy- CLINIGENE

Coordinator: Odile Cohen-Haguenauer (Paris)

The field of gene therapy has matured and the prospects are exciting and hopeful, particularly since some treatments have now been shown to be effective in the clinic. However, precise quality and safety standards for clinical gene transfer have yet to be defined. In this context, defining optimal methods for the production of standard vector systems would pave the way for accelerated development and improved safety. This would be of enormous value to industry, individual investigators and regulators.

The goal of this proposal is the creation of a European Network for the Advancement of Clinical Gene Transfer and Therapy (CLINIGENE) integrating multidisciplinary research and development in gene therapy as well as mobilising all major stake holders involved in the development of gene therapy medicinal products: academia, industry, regulatory bodies, clinics and patients. The network will generate platform databases for particular vectors with respect to their safety and efficacy to ensure product manufacturing according to well-defined quality and safety standards in order to accelerate clinical trials. This will be achieved by compiling all available information and then ranking test and control methods by comparison, and through validation by expert partners.

The joint programme of activities comprises 1. Integration activites: sharing facilities, exchange and high-level training of personnel, e-communication and collaboration with the ESGT. 2. Research activities: six horizontal activities serving integration towards the generation of reference/standard profile data-bases – AAV, γ-retrovirus, lentivirus, adenovirus, genetically-modified cells & non-viral vectors – and four vertical activities defining a path to optimised clinical protocols – quality and efficacy (manufacture), safety (pharmtox and virus safety); pre-clinical models and novel assessment tools, clinical trials. 3. Dissemination activities: training, high-level education, communication (including a web-site with scientific & medical data-bases) and management of shared information and intellectual property rights.Within a strong integration plan, the Network is planning for flexibility in order to adapt to: (i) progresses recorded in a stepwise manner and (ii) novelty arising during the CLINIGENE workprogramme.