The Demand for new Therapies against Chronic Liver Diseases
Chronic liver diseases (CLD) and their end-stages, cirrhosis and hepatocellular carcinoma (HCC), are leading causes of morbidity and mortality worldwide with enormous socio-economic costs. Patients with liver cirrhosis are at high risk of deadly hepatic failure and over 80% of HCC develop on a cirrhotic background. HCC ranks as the 5th most common cancer and with > 600,000 deaths per annum it constitutes a major global health problem. The main etiologies of CLD are chronic HCV and HBV infections, alcohol abuse and non-alcoholic steatohepatitis (NASH) as a result of the metabolic syndrome taking epidemic proportions. Liver transplantation is currently the only available therapy for terminal liver failure. With donor organs being limited, preventive measures and development of new therapies for CLD are in high demand. Prevention aims at discarding the source of damage. In alcoholic liver disease (ALD), this obviously breaks down to avoiding further alcohol consumption. Addictive behaviour of patients, however, puts a serious limitation to the efficiency of this prevention strategy. HBV and HCV infections, representing about a third of CLD’s etiologies, are combatted with virostatic treatments, thus improving patient conditions to some extent. The infections cannot, however, be fully abrogated, severely narrowing down efficiency of this therapy for this CLD subset. In the absence of novel therapies, CLD will continue to be a major medical problem with enormous social and economic costs.
Dissecting Cellular and Molecular Disease Mechanisms is Key to Development of Novel CLD Drugs and Therapies
Viral activity, chemical toxicity and metabolic overload cause damage and death to hepatocytes. This liver injury triggers a cascade of molecular and cellular reactions geared towards damage limitation, removal or repair of damaged cells, defence against further infection, tissue repair and regeneration. Central in the natural response to the injury are inflammation, as induced by a large battery of signalling molecules and executed by a variety of dedicated cells, and repairby activated myofibroblasts, which produce the fibrous tissue needed for restoring damage, and parenchymal cell proliferation, which in combination, release the enormous natural regenerative potential of the liver. In CLD, wound healing and tissue remodelling processes go awry, resulting in fibrosis and ultimately cirrhosis, the platform on which HCC and deadly hepatic failure develop. At the cellular and molecular level, the multistep process of a progressive CLD is reflected in complex modulation of intracellular signal transduction circuits, altered cell-cell communications and, more drastically, an altered differentiation state of most liver resident cell types. Evidently, dissecting these pathways is critical for development of drugs and therapies. It is well recognized that the cytokine TGF-β plays a pivotal role in the sequence of events leading to end-stage CLD, but the complexity of the underlying aberrant responses in the cells and the organ that lead to the drastic changes seen in CLD and HCC is poorly understood.
A broad spectrum of scientific and technological capacities is needed to accomplish the goal of discovering drugs and treatment modalities for CLD and HCC. Following bi-lateral interactions, IT-LIVER’s partners have in the past year convened in person (Barcelona December 3rd , 2009) and in several videoconferences, to conclude that individual groups in European Universities, Research Institutes and private Companies may excel in the components of the requisite skills spectrum, but that no European network exists that brings together in an integrative way the expertise to provide a comprehensive research and training programme with the goal to combat CLD by (i) unravelling the molecular and cellular complexities of TGF-β responses in CLD progression and (ii) rationally designing and discovering CLD drugs, drug delivery systems and CLD treatment modalities.
As a result, there is a lack – in academia and industry alike - of internationally oriented researchers and research leaders, capable of seamless and bi-directional transfer of goal-oriented scientific knowledge and technologies between the basic, translational and clinical research and industrial capacities; a conditio sine qua nonfor effectively and efficiently combating CLD and HCC and alleviate its medical and socio-economic burdens.
Consequently, this ITN formulated the mission to provide a multidisciplinary and intersectorial Research Training Programme for talented young researchers, so as to prepare them for leading roles in CLD research and drug discovery in European industry and academia.
There are 8 outstanding European academic partners and 4 industrial partners in the ITN with complementary expertise to span the full spectrum of basic, translational and (pre)clinical research training. The academic partners are well recognized as leaders of European research teams working in TGF-β and their role in liver diseases, with the potential to establish world leadership in the field, mainly due to the competitive edge provided by EU support for intensive collaboration of a critical mass of researchers from different disciplines. The academic partners offer different, but complementary scientific knowledge and technological platforms in molecular cell biology, preclinical models and drug discovery and delivery, which will provide ESR/ERs with the most advanced training possibilities. Next to their scientific and technological skills, the industrial partners provide excellent platforms for ESRs and ERs to obtain as part of the ITN’s Training Programme, training in industrial innovation, entrepreneurship, intellectual property handling, management and marketing. Finally, the partners fully recognized the importance of transcending their own (sub)disciplines and sectors to accomplish the ITN’s mission.
The specific aims of the ITN Training programme are to:
- provide talented early stage and experienced researchers (ESR/ER) a research training programme aimed at acquistion of
- state-of-the-art knowledge of the components of the skills spectrum needed to combat CLD, i.e. science and technologies of basic molecular liver cell biology, drug discovery and delivery systems and development of preclinical models and (pre)clinical treatment modalities.
- the ability to assimilate the individual components of the skills spectrum such that they will be able to oversee and in a goal-oriented manner direct the multisectorial process of combatting diseases in general, but CLD in particular.
- employability of its ESR/ERs in the higher ranks of academia and industry by enhancing their transferable skills e.g in writing and communication and intellectual property management, valorisation, enterpreneurship.
- strengthen intersectorial research cooperation to advance our understanding of the molecular and cellular mechanims of CLD progression and to translate this knowledge into drug discovery and treatment modalities.
The aims of the training network will be channelled through the following activities:
- Organizing different events (seminars, secondments, etc) which will provide specific and complementary training in skills essential for the early-stage researchers and give them a competitive edge.
- A multi-disciplinary research programme for the study of TGF-β in liver diseases that will ensure a solid foundation in research technology and methods through two interacting and complementary research subprogrammes:
- Molecular Mechanisms: Investigation of the complex regulatory networks that control liver development and pathology and the role of TGF-β in these processes. Design of appropriate strategies and technology to analyze the deregulation in the TGF-β pathway occurring in human CLD and especially in fibrosis and HCC.
- Target Discovery and Preclinical Models: Design of new drugs to target TGF-β signalling (targeting, monitoring). New therapeutic approaches for drug delivery.
Our acronym IT-LIVER relates to Inhibiting TGF-β in Liver Diseases.