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  • br Rare diseases of the

    2019-07-11


    Rare diseases of the liver There are over 7000 rare diseases, but only ~600 (~10%) have approved therapies. A disease is rare, by definition, if it affects fewer than 200,000 individuals in the US, and although individual diseases may be rare, collectively, they contribute to a significant portion of morbidity, particularly in pediatric populations affecting over 30 million people worldwide. There are many challenges to conducting clinical development for rare diseases, including small numbers of patients with the disease, few disease experts, and limited resources available for their study. Approximately 80% of rare diseases are genetic in origin but only a small percentage have ongoing basic, translational or clinical research. Although most people are aware of common liver diseases such as cancer and hepatitis, there are over 100 different types of liver diseases, and many of them are rare inherited errors of liver metabolism, and many affect pediatric populations [10].
    Conclusion The modeling of human diseases in animals has been critical for the development of therapies. In most cases though, animal models do not fully capture all aspects of the physiology of human diseases and that has partly led to a very low success rate from clinical testing to approvals. The low predictive power of animal models is particularly concerning for rare diseases. As highlighted in this review of a select group of rare liver disorders, differences in animal and human physiology, inter Lactacystin (Synthetic) background strain, and genetic predisposition all contribute to the variations and ability to fully predict outcomes in humans. Despite the challenges, advances have been made in drug development for several of the rare liver disorders leading to investigational agents currently undergoing clinical development or to the approval of new medicines. However, with only about 10% of rare diseases with an approved therapy, the need remains to continue refining existing models or develop new more relevant models. For example, larger animal species such as canine, feline or porcine models, complementary ex-vivo technologies such as disease relevant 3D tissue models, or investments in platform approaches for therapeutic development, for example, liver interventions that address general processes such inflammation, fibrosis and accumulation of proteins, lipid and metals that are common across the stages of liver disease, regardless of the initial insult.
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    Acknowledgements This work was supported by the Intramural Research Program of the National Center for Advancing Translational Sciences, the National Institutes of Health.
    Introduction
    Animal models
    Animal models in comparison Each model has specific features, advantages and disadvantages and thus, the animal model should be chosen according to the research questions that want to be answered. Species, strain and sex should be chosen in regard to the main endpoint parameter of the study while comprising significant influence on the phenotype of the model. The length of timeline of each model should be chosen by the stage of disease which is in the focus of interest. For the inflammatory phase of cirrhosis and early fibrogenesis a shorter timeline is recommended, whereas a longer timeline is better suited for advanced fibrosis or portal hypertension. In this regard, consider treatment settings: prevention treatment vs. therapeutic/regressive treatment. In addition, the different application routes, administration schedules, environmental or housing condition may influence the severity of disease as most evident from the CCl4 and TAA intoxication models where some heterogeneity is observed in the fibrogenic and inflammatory response. Even the experience of the experimenter, different manufacturers, or the storing of the diets have an impact on the overall performance. Therefore, the establishment of an animal model at a laboratory needs time and effort. At last, the potential for disease reversibility of an animal model is essential to answer questions concerning the mechanisms involved in resolution of hepatic inflammation, steatosis or liver fibrosis regression (Table 1).