European Journal of Molecular & Clinical Medicine

On behalf of the European Society for Translational Medicine (EUSTM) and Global Translational Medicine Consortium (GTMC), we are pleased to introduce New Horizons in Translational Medicine (NHTM), our official publication. Translational medicine Is an interdisciplinary field that unites multiple disciplines and expertise in order to enhance the efficacy of prevention, diagnosis and treatment of clinical conditions thereby improving global healthcare. Translational medicine has gained significant importance due in large part to its influential role in moving benchside results to bedside therapies and improvements in community health

The integration of clinical and molecular sciences with advanced engineering sciences is moving the world towards a new generation of life science where physiological and pathological information from the living human body can be quantitatively described in silico via biocomputing across multiple scales of time and size and through diverse hierarchies of organization – from molecules to cells and organs to individuals. The development of the Virtual Patient will change conventional medicine, which has been based upon experience and expectation, into “predictive medicine” that will have the capacity to develop solutions based upon prior understanding of the dynamic mechanisms and the quantitative logic of human physiology. Drug discovery, medical and welfare apparatus, and clinical trials in silico will improve the development of products with higher efficiency, reliability and safety while reducing cost. They will also impact upon knowledge-intensive industries. Such program aims at playing a key role in this new area, by sharing and generating solutions as well as human resources contributing to establishment of “in silico medicine” as a basis of the predictive medicine within an international framework. In the long-term, computational physiological models will be refined, linked and validated until they are capable of providing essential predictions to clinicians when healthcare decisions need to be made. As the amount of data reinforcing the models grows, predictions will become more and more patient-centred, with models migrating from statistical, average models to physiological and mechanistic models informed by the unique characteristics of the patient. Systems Patientomics will propose new ways of combining this rich patient information space in a highly visual, coherent, meaningful way and of generating new clinical information by blending and fusing existing information, ultimately creating a “Patient Avatar” capable of supporting the medical professional by producing new clinical knowledge emerging from the integration of patient- and population-specific information. Focal points: Benchside Quite a few experimental biologists, functional and statistical genomics researchers, involved in developing new measurement technology for biology, and even molecular systems biologists, feel that that computational methods are not relevant for their own research goals. For the lion’s share of those cases where these research goals are rationalized by their potential value for predictive, preventive and participatory medicine this is a misconception. Bedside Systems computational approaches should be a routine part of the clinical arsenal for the diagnosis, planning and executing of therapeutic interventions. This must include the incorporation of relevant training in medical school curricula. Industry Collaborations to be developed across the breadth of the stakeholder groups involved in public health, from public health providers and patient groups, to researchers, scientists, funders and industry. Community Development of an ethical and legal framework (establish common rules and principles for data acquisition/sharing/integration/reduction to practice, define how to achieve patient consent, to respond to fears of misuse of provided data, define solutions for data protection/open innovation).

Despite large investments in drug development, the overall success rate of drugs during clinical development remains low. One prominent explanation is flawed preclinical research, in which the use and outcome of animal models is pivotal to bridge the translational gap to the clinic. Therefore, the selection of a validated and predictive animal model is essential to address the clinical question. In this review, the current challenges and limitations of animal models are discussed, with a focus on the fit-for-purpose validation. Moreover, guidance is provided on the selection, design and conduct of an animal model, including the recommendation of assessing both efficacy and safety endpoints. In order to improve the clinical translation, the use of humanized mouse models and preclinical applications of clinical features are discussed. On top, the translational value of animal models could be further enhanced when combined with emerging alternative translational approaches. Focal points: • Bedside Animal models are essential for translation of drug findings from bench to bedside. Hence, critical evaluation of the face and predictive validity of these models is important. Reversely, clinical bedside findings that were not predicted by animal testing should be back translated and used to refine the animal models. • Benchside Proper design, execution and reporting of animal model results help to make preclinical data more reproducible and translatable to the clinic. • Industry Design of an animal model strategy is part of the translational plan rather than (a) single experiment(s). Data from animal models are essential in predicting the clinical outcome for a specific drug in development. • Community Review, standardization and refinement of animal models by disease expert groups helps to improve rigor of animal model testing. It is important that the applied animal models are validated fit-for-purpose according to stringent criteria and reproducible. • Governments As during drug development fit-for-purpose animal models are key for success in clinical translation, financial investments and support from the government to develop, optimize, validate and run such translation tools are important. Over time, this will be of benefit for patients and healthcare institutions. • Regulatory agencies Preclinical testing of a drug in an animal model is not a prerequisite for regulatory agencies before entering clinical trials, but does unquestionably provide valuable data on the expected clinical performance of the drug. Hence, testing in animal models is largely recommended from both a business and patient perspective. In addition, inclusion of safety parameters in animal models will help to build the required safety data package of drugs in development.

Therapeutic targets for neurodegenerative conditions are constantly emerging. Diseases such as amyotrophic lateral sclerosis and Huntington׳s disease are multifactorial and involve dysfunction of various cellular pathways. Protein aggregate formation is one of the crucial pathological signs of cellular dysfunction, and is characteristic of many neurodegenerative conditions. Proteins recruited to these aggregates are thought to play a role in formation of the pathogenic inclusions. This review aims at exploring the current evidence for protein aggregation and the role for Arfaptin2, as a candidate factor contributing to the formation of aggresomes and a potential therapeutic target in motor neuron disease. Focal points • Bedside Understanding the multifactorial nature of the pathogenesis of neurodegenerative diseases will contribute to the research into the therapeutic targets of the disease, allowing more factors to be discovered in patients affected by the debilitating disorders of the nervous system. • Benchside Collaborative efforts in investigating the causes and pathways of neurodegeneration are likely to increase the chance of discovering novel therapy approaches that may be utilised in more than one type of neurodegenerative disorders. • Industry The application of the novel therapeutic target such as Arfaptin, and other proteins associated with protein aggregates, to the development of therapy approaches may open new avenues in drug discovery for neurodegenerative diseases. • Community Diseases of central nervous system bear a great impact on the quality of life of the patients and their carers. Promoting the awareness through communicating the current state of the research provides a form of a mental support to those affected by these conditions. • Regulatory agencies The need for funding the research into the basic understanding of the mechanisms involved in the pathogenesis of the neurodegenerative conditions must not be overlooked. The research into the cellular defects provides with invaluable findings about the healthy and diseased cell functioning.

Focal points • Bedside Targeted pharmacologic disruption of PAI-1 function with small molecule inhibitors may have general applicability for the treatment of fibroproliferative disorders, in general, and vascular disease, in particular. The development orally compatible drugs would likely simplify delivery and patient compliance. • Benchside It is apparent that PAI-1 is a multi-functional SERPIN, affecting such diverse physiological and pathophysiological processes as smooth muscle cell growth, migration, survival and pericellular proteolysis activity. Clearly, PAI-1 functional blockade has widespread clinical implications that are not restricted to one aspect of the tissue response to injury. • Industry The original small molecule panel of PAI-1 inhibitors derived from a collaboration between basic scientists and, largely, cardiovascular disease-oriented medical chemists as well as pharmaceutical investigators. This collegial relationship is expected to expand as it is evident that PAI-1 inhibition has generally utility in the treatment of cardiovascular diseases, tissue fibrosis (in particular, the renal and pulmonary systems) and cancer.