Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders Proceedings of a Workshop (2017) / Chapter Skim
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4 New Modeling Approaches for Nervous System Disorders
4 New Modeling Approaches for Nervous System Disorders
Pages 23-32
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From page 23... ...
. • While traditional cultures of neurons derived from iPS cells may be too simple to study complex central nervous system disorders such as schizophrenia and autism, three-dimensional (3D)
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From page 24... ...
. • Knowledge gained through studies applying iPS cells, non human primate models, and QSP to orphan or monogenic dis eases may advance drug development for nervous system disor ders through better clinical study design (Feng, Jensen, Rubin)
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From page 25... ...
He noted that in an informal survey of pharmaceutical company partners they found about half indicated they would be willing to proceed without in vivo efficacy if they had efficacy in iPS cells, in vivo toxicology was acceptable, and a good target engagement biomarker was available, he said. iPS cells enable scientists to move beyond pathology and emphasize prediction, said Finkbeiner.
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From page 26... ...
They are also mining imaging data and using machine learning approaches to extract information and develop quantitative, dynamic, multidimensional measures of cellular health or sickness. However, a number of obstacles remain to be addressed to realize the potential of iPS cells as drug discovery platforms, noted Finkbeiner.
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From page 27... ...
Compared to organoids, spheroids are structurally simpler, but more consistent and can be produced by the billions, said Rubin. They are made by taking uniform clusters of iPS cells and exposing them to different factors that induce neuronal differentiation.
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From page 28... ...
However, marmosets have the advantage of a short reproductive cycle, reach sexual maturity earlier, and give birth to twins or triplets twice per year, making it much easier to generate a large cohort for studies, said Feng. At the Massachusetts Institute of Technology and the Broad Institute, Feng and colleagues have set out to establish a genetic engineering platform for brain disorder research and drug discovery, using genetically engineered marmosets and the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)
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From page 29... ...
However, he predicted that as more information about the genetics of complex disease becomes available and gene editing technology and other genetic tools improve, it will be possible to generate multiple mutations and/or multiple knock-ins in one injection per animal, map disease-relevant cell type–specific molecular changes, and identify cell type–specific targets for correcting circuit dysfunction. COMPUTATIONAL QUANTITATIVE SYSTEMS PHARMACOLOGY MODELING OF BRAIN CIRCUITS Computational modeling may be an additional tool to expedite progress in drug development, according to Hugo Geerts, chief scientist at In Silico Biosciences.
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From page 30... ...
Geerts maintained that QSP can help answer critical preclinical and clinical questions in drug development, including those related to target identification, selection of a clinical candidate, demonstration of target engagement, determination of what constitutes a clinically meaningful outcome, dosing parameters, patient selection, and impact of genotypes and co-medications of clinical dose response.
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From page 31... ...
Frances Jensen suggested that applying these models to the study of orphan diseases, which are relatively pure disorders with more homogeneous endophenotypes, might provide the best opportunity to advance these new models, in part because studies can be much smaller and enroll more homogeneous participants. She also suggested that working with non-animal and animal models in tandem might expedite discovery.
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