Improving and Accelerating Therapeutic Development for Nervous System Disorders Workshop Summary (2014) / Chapter Skim
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3 Target Identification
3 Target Identification
Pages 25-40
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Speakers and participants discussed ways to improve this starting point and thereby accelerate therapeutic development through the use of stem cells, humanized animal models, increased knowledge of genetics, and imaging.
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, in addition to the use of stem cells to create humanized animal models. Induced Pluripotent Stem Cells iPSCs provide a valuable tool for studying diseases and understanding pathways needed to develop potential therapeutics, said Lawrence Goldstein, director of the University of California, San Diego (UCSD)
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A participant noted that cellular readouts may be difficult to obtain for neuropsychiatric disorders, and, as a result, researchers might turn to physiological and imaging readouts to subset patient populations. A few participants noted that although there will be an influx of useful genetic data pouring into the field, researchers are, at times, unaware of specific disease phenotypes -- making drawing conclusions from data challenging.
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Adrian Ivinson, director of the Harvard NeuroDiscovery Center at Harvard University, discussed a similar approach in which his laboratory tested its library of compounds against cells from 50–200 patientderived, induced pluripotent stem neuronal cell lines. It is a departure from the standard convention of testing thousands of compounds against one assay designed to model the disease process.
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Researchers are trying to understand how mutations in these genes induce motor neuron degeneration and why motor neurons are selectively sensitive to the effects of mutation when other cells are not. The answers to these questions have been slow in coming largely because of a lack of animal models.
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Because of this, understanding how regulatory regions change the expression of nearby genes by using human iPSCs or human embryonic stem cell–derived neurons might lead to greater success compared to conventional animal models. In the end, Eggan advocated for a measured approach and suggested that rather than overinvesting in one hypothesis or target, a broad-based platform of investment that raises all areas could be beneficial to accelerate the development of therapeutics.
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GENETICS Using genetics as a tool to better understand variations in patient populations compared to healthy populations may facilitate the identification of novel therapeutic targets for nervous system disorders. Through DNA sequencing, researchers have the ability to locate molecular sites associated with specific diseases.
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. In a study of FOXP2, a transcription factor implicated in human speech and language dysfunction, a change of two amino acid sequences leads to significant functional deficits, largely due to FOXP2's regulatory role (Konopka et al., 2009)
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David Goldstein and colleagues also found that the de novo mutations playing an causative role could be grouped into functional categories. For example, six de novo mutations were found in GABA receptor subunits.
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Molecular mechanisms of association can be studied in cellular and animal models once these variations are understood. Weinberger provided two examples illustrating this roapmap: a metabotropic glutamate receptor and a novel potassium channel.
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A better understanding of the genetic underpinnings of nervous system disorders has the potential to facilitate drug development through improved target identification. 6 See http://www.libd.org.
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Translational Tools for Drug Development for Mood Disorders Wayne Drevets, scientific vice president and disease area leader in mood disorders at Janssen Pharmaceutical Companies of Johnson & Johnson, discussed several translational tools and models relevant to therapeutic development in mood disorders. Drevets is currently studying mood disorders with bioimaging modalities due to the limited number of animal models that fully recapitulate the behavioral and biological abnormalities of mood disorders.
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Drevets and his colleagues are working on increasing studies conducted on people with depression rather than using old behavioral assays in animal models. Identifying Molecular Targets in Traumatic Brain Injury Ramon Diaz-Arrastia, professor of neurology at the Uniformed Services University of the Health Sciences, spoke about the use of imaging to identify new molecular targets in traumatic brain injury (TBI)
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Anti-Nogo monoclonal antibodies have witnessed some measure of success in animal models of TBI and spinal cord injury (Freund et al., 2007; Marklund et al., 2007)
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Small and colleagues conducted neuroimaging studies in humans to further understand hippocampal patterns for AD and schizophrenia, followed by validation studies in animals. In a series of experiments, Small and colleagues sought to distinguish cognitive dysfunction in AD versus normal aging using functional MRI (fMRI)
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Imaging is a tool that can be used in several facets of drug development for nervous system disorders. Particularly for target identification, researchers are able to visually map areas of the brain that are associated with specific disorders, which in turn may help to objectively determine potential targets.
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