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  • Temozolomide One of the important steps


    One of the important steps and challenges in translation is the appropriate modeling of human disease using both in vitro and in vivo systems. Animal models have played a critical role in the understanding of disease pathophysiology, target identification/validation, and in vivo evaluation of novel therapeutic agents [5]. In drug development, animal models are also used to bridge the translational gap to clinic by addressing important parameters of in vivo pharmacology of the drug, including efficacy, mechanism of action, establishing the pharmacodynamic/pharmacokinetic (PK/PD) relationships, estimating clinical dosing regimens, and determining safety margins and toxicity. It is generally accepted that the majority of animal models are not able to fully recapitulate all aspects of the human clinical condition. It is estimated that up 70% of new drug candidates fail in Phase 2 and of those that survive to Phase 3, another 50% fail, the majority of which is due to a lack of safety and efficacy [6, 7]. One of the largest hurdles to a higher success rate in drug development is the low clinical predictability of the existing disease models. In most cases, the positive efficacy results observed in in vivo preclinical studies using animal models that do not reproduce in clinical development. The differences in disease phenotypes are often attributed to physiological differences in species and/or genetic background [5, 8]. Notably, in a comparative analysis of liver transcriptomes between human, mouse, and rat, it was found that the expression profile of homologous genes was significantly different suggesting there are divergences in liver function [9]. To overcome limitations of in vivo models, there is now considerable efforts towards the development of in vitro systems that mimic native human tissues for drug testing. Experimental models under development use human induced pluripotent stem Temozolomide (IPSCs), 3D tissue models such as spheroids, organoids, and bioprinted tissues, and attempt to recreate the physiological complexity in native tissues which is not available in traditional 2D cell models in a dish. One of the major advantages of these approaches is that the process of “reverse” translation is engaged starting with clinical samples from patients, and then creating a model system to test drug candidates which are more relevant for therapeutic development. These new cell technologies will provide a combination of different pre-clinical models that may eventually provide more robust pre-clinical data that will enable a better selection of drugs candidates with better prediction of human responses in the clinic [5], for example, a mouse liver disease model complemented by an ex vivo human liver cell culture or a 3D printed liver tissue using human iPSC cells. It is critical to have high quality and well-validated models that are reflective of the human disease condition, as determined by using the relevant disease markers, when designing and testing novel treatments in pre-clinical studies so that the results are predictive of efficacy in humans. In vitro and in vivo models with high predictive power will provide data to enable more effective decision-making during the selection of drug candidates, and hopefully have a higher probability of becoming approved medicines. Furthermore, a higher translational value could be better achieved when combining these systems with other approaches such as quantitative systems pharmacology, biomarkers, efficacy endpoints, natural history studies, and or other clinical data. Here we will focus on reviewing the state of existing in vitro and in vivo models used to study a select group of inherited rare liver diseases, including alpha-1-anti-trypsin deficiency (AATD) and hereditary hemochromatosis (HH), the two most common inherited liver diseases. In addition, the review will examine how closely the models mirror the human disease, and their use and translatability in any previous or currently ongoing therapeutic development efforts. This review will not address liver diseases where the primary cause is cancer, autoimmune, infections, alcohol-drugs (prescribed and illicit) and diet-induced as well as idiopathic in etiology.