Pre-clinical evaluations often provide the rationale for therapeutic assessments in humans; however in many diseases an agent found successful in animal models does not show efficacy in human subjects. Adapting methods of clinical trial performance will likely improve the success rate of therapeutics to ultimately achieve human use. Keywords: myasthenia gravis clinical trials therapeutic development preclinical assessment animal models Introduction The armamentarium of immune suppressive agents used in the treatment of autoimmune myasthenia gravis (MG) has largely emanated from the transplant literature and experience with the use of these drugs in the treatment of other autoimmune disorders.(Sieb 2014 At first glance this may seem surprising given that most common antigenic targets of the autoimmune response in Doramapimod (BIRB-796) MG are well known and the availability of a well-studied animal models of MG either experimental autoimmune myasthenia gravis (EAMG) produced by immunization with the acetylcholine receptor (AChR) or muscle specific tyrosine kinase (MuSK) or passive transfer of autoantibody (PTMG).(Baggi et al. 2012 Berrih-Aknin and Le Panse 2014 With the exception of the C5 complement inhibitor eculizumab (Howard et al. 2013 which was originally found to be effective in PTMG rat (Zhou et al. 2007 none of the therapies currently used for treatment of MG emerged from pre-clinical work in animal models. Upon closer inspection however it is clear that there are limitations to EAMG as a tool for pre-clinical assessment Doramapimod (BIRB-796) of Doramapimod (BIRB-796) potential therapeutic agents Rabbit polyclonal to BIK.The protein encoded by this gene is known to interact with cellular and viral survival-promoting proteins, such as BCL2 and the Epstein-Barr virus in order to enhance programed cell death.. and these issues will be discussed in greater detail elsewhere in this special issue. Here we focus on how experience from clinical trials in patients with MG might be used to enhance the utility of the EAMG rodent models for pre-clinical evaluation of therapeutics prior to their advancement into human clinical trials. Trial Design Human clinical trials are carefully designed experiments with significant attention to important methodological issues. For example eligibility criteria are defined in order to yield an appropriate study population; treatment allocation is randomly assigned; primary and secondary outcome measures and endpoints are pre-specified; outcomes are assessed by an evaluator blinded to treatment assignment; and due consideration is given to the sample size needed to demonstrate the minimal clinically important difference in Doramapimod (BIRB-796) outcome in order to ensure that the trial has adequate power to detect the treatment effect of interest. The rigor of pre-clinical therapeutic studies in EAMG rodent models would benefit from attention to these methodological issues. Eligibility Criteria Because human MG has clinical and pathophysiological heterogeneity that is influenced by age and gender.(Berrih-Aknin et al. 2014 clinical trials for MG typically restrict enrollment to individuals in a specified age range although generally they are open to both sexes. Animal investigations typically utilize rodents that are in early adulthood and utilize only one sex. Two year old rats have been found to be resistant to development of weakness produced by active immunization with ACHR.(Hoedemaekers et al. 1997 Old female rats demonstrated greater loss of AChR than male counterparts but still did not show weakness compared to young rats. The effects appear to result from the properties of the neuromuscular junction rather than age-related changes of the immune system. To align the preclinical studies to those in MG the National Institutes of Health has recommended that preclinical studies be carried out in animals of both sexes (Clayton and Collins 2014 Eligibility criteria for human MG clinical trials typically exclude patients with purely ocular disease as well as those with impending or actual myasthenic crisis and require that patients have some minimal degree of weakness (e.g. Quantitative MG score of at least 12 points). A similar approach might be adopted in the rodent models requiring that immunized animals develop some minimal degree of weakness (e.g. grade II). It may be far more difficult for example to demonstrate a clinical effect in terms of improved strength in animals that do not have at least grade II weakness prior to administration of the potential therapeutic agent. Randomization The principal goal of randomization is to control.