Improving the Utility and Translation of Animal Models for Nervous System Disorders Workshop Summary (2013) / Chapter Skim
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7 Summary of Workshop Topics
7 Summary of Workshop Topics
Pages 67-76
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From page 67... ...
Studies in animals allow, for example, evaluation of drug targets, testing of pharmacokinetics, metabolism, distribution of investigational compounds, and prediction of the dose that will be maximally efficacious and yet still tolerable and safe. Animal studies expand the understanding of the nervous system diseases and disorders in a defined system and allow researchers to draw links to clinical pathways and formulate hypotheses for human testing, In summary, said session chair Stevin Zorn, although we can learn much from animal models, it was emphasized in the presentations and discussion that what we learn depends heavily what questions are asked, 1 The topics highlighted in this chapter are based on the summary remarks made by each session chair during the final workshop session and at the end of his or her session.
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From page 68... ...
In other words, these animals are modeling specific perturbations in an effort to understand the biology and assess potential therapies. Bringing a new drug to market has numerous challenges and significant costs and many potential therapies fail to meet expectations in Phase III clinical trials.
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From page 69... ...
DISORDER-FOCUSED BREAKOUT DISCUSSIONS To foster more in-depth analysis of the translational success of animal models, the second session of the workshop featured concurrent breakout discussions on six areas of neuroscience research: neurodegeneration, Alzheimer's disease, stroke, schizophrenia, addiction, and pain. Based on the breakout summaries provided by each group moderator when the full workshop reconvened (see Chapter 3)
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From page 70... ...
Therefore, the next steps for improving translation of animal models may differ depending on the current state of knowledge about the basic biology of diseases and disorders. Adequacy of Models Hodes recalled the summary from the stroke breakout group, where it was noted that adequate animal models of stroke exist, but translation of the science from animal model to humans has failed.
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From page 71... ...
STANDARDIZATION Issues surrounding the standardization of animal models were discussed from the perspective of preclinical models of anxiety, cognitive assays, and Alzheimer's disease models. Session chair Walter Koroshetz pointed out an overarching concern for these and all models is that the process of tool development and standardization of models is not easily funded or staffed.
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From page 72... ...
Koroshetz reiterated a list of best practices for preclinical animal studies offered by Mucke, which included blind coding of all analyses and allocations, carefully matching experimental and control groups, rigorous statistical approaches, reproducing results in independent cohorts at different times and in different conditions, using multiple outcome measures, quality control of animal models, validating across models and in the human condition, and including sensitive positive controls to help eliminate false negatives. Several participants noted that a positive control need not necessarily be a compound, but rather, some demonstration that the assay is as sensitive as expected to pharmacological manipulations.
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From page 73... ...
Clinical trials were conducted based on the animal study showing control of EAE by inhibition of TNF, but the trial results soon confirmed the animal study showing exacerbation of disease when TNF is blocked. Another example described how neuroimaging tools have allowed us to understand and exploit the fact that the functional components of hippocampal circuits are very similar in their core functions across animal models and humans.
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From page 74... ...
He continued on the theme that discussions about animal models should focus on what is being predicted. This means not attempting to predict Phase III clinical trials outcomes, but more toward predicting Phase IIA results.
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From page 75... ...
It was also suggested that researchers are misleading each other with these "therapeutic misconceptions." In this context, it was suggested that authors of manuscripts, reviewers, and journal editors should carefully examine the weight assigned to published results. It was reiterated that clinical trials are conducted for a particular disease and geared toward a drug label indication for treating specific symptoms in the context of the disease.
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From page 76... ...
At each step of the therapeutic development pathway, speakers and participants suggested specific areas for improvement, including the validation of targets, the design of experiments, how results are statistically analyzed, and the way in which positive and negative results are reported. Many participants supported increasing cross-sector collaboration, strengthening training programs and improving the reproducibility of research with a goal of improving translational efforts.
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