Improving the Utility and Translation of Animal Models for Nervous System Disorders Workshop Summary (2013) / Chapter Skim
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3 Translation from Animal Models to the Clinic: Case Examples from Neuroscience Research
3 Translation from Animal Models to the Clinic: Case Examples from Neuroscience Research
Pages 21-32
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From page 21... ...
ANIMAL MODELS FOR ALZHEIMER'S DISEASE In discussing current animal models for Alzheimer's disease it is important to think about the human phenotype and what is being modeled in terms of the animal phenotype. The moderator, Bradley Hyman, professor of neurology at Harvard Medical School, said that animal models of 21
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From page 22... ...
Hyman questioned the hypotheses tested in humans that do not have exact correlates in animal models (e.g., differences in when amyloid deposition occurs between animal models and in human disease)
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From page 23... ...
Robert Ferrante, professor in the departments of neurological surgery, neurology, and neurobiology at the University of Pittsburgh, noted that much of this breakout group's discussion centered on standardization of models and whether they accurately reflect neurodegenerative diseases. Ferrante suggested that current animal models for Huntington's disease and ALS may accurately reflect not only pathophysiological mechanisms of human disease, but also neuropathology and behavioral phenomena.
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From page 24... ...
In discussion whether animal models accurately reflect human neurodegenerative disease, the issue was raised as to whether animal model studies might be replaced with more Phase 0 clinical trials in humans. In this regard, there was a call for the identification of pharmacodynamic markers and biomarkers that are clearly reflective of the disease.
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From page 25... ...
Despite the relative suitability of the animal model for the study of stroke, clinical trials have not produced effective treatments and many pharmaceutical companies have scaled back or abandoned stroke research programs. A few participants suggested that failure in the clinic is partly because endpoints used in preclinical animal studies are different from those used in clinical trials.
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From page 26... ...
ANIMAL MODELS FOR ADDICTION Athina Markou, professor in the department of psychiatry at the University of California, San Diego, described the development of the smoking cessation drug varenicline as an example of successful development of a therapy for addiction. Markou speculated, however, that the success of varenicline in clinical trials is attributable more to the fact that there was a very strong theoretical rationale and less to the translation of preclinical animal studies.
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From page 27... ...
In fact, genetic studies have provided some potential targets and it was suggested that one way to move forward is to try to over- or under-express these genes in mouse models and to study the heterogeneity of addiction development. Finally, participants in the breakout session discussed concerns with clinical trials.
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From page 28... ...
First, however, there needs to be reliable and objective assays for humans that can predict a clinically significant change such as worsening or improvement in the patient's clinical profile. For animal modelers, clinical outcomes such as reduction in symptoms based on subjective scales are not useful.
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From page 29... ...
Moore summarized the main points of this breakout session as • Animal models and human clinical research inform each other. • Control, or intact, model systems are useful for target validation and pharmacodynamics.
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Many participants indicated that much can be learned from genetic models in mice that might inform research on the human condition. In summary, participants in this breakout session raised the following issues with regard to animal models of pain: • Many existing animal models of pain might be more useful if re searchers ask the right questions.
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From page 31... ...
ANIMAL MODELS ADDRESSING NEURODEVELOPMENT In the open discussion following the breakout group summaries, a participant raised another subarea of neuroscience research as an offshoot of the discussions of models for schizophrenia and addiction -- animal models of what may essentially be developmental disorders. Moore pointed out that although models of schizophrenia in adult animals are used for pharmacologic studies, knowledge of the epidemiology of schizophrenia has led to the development of models where the perturbation is made quite early in development, when risk factors for the disease come into play.
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From page 32... ...
Therefore, it would be important to extend animal models of addiction to this developmental stage as well.
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