Evolving towards a human-cell based and multiscale approach to drug discovery for CNS disorders
A disruptive approach to therapeutic discovery and development is required in order to significantly improve the success rate of drug discovery for central nervous system (CNS) disorders. In this review, we first assess the key factors contributing to the frequent clinical failures for novel drugs....
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2014-12-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fphar.2014.00252/full |
| _version_ | 1819144040827846656 |
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| author | Eric eSchadt Sean eBuchanan Kristen eBrennand Kalpana eMerchant |
| author_facet | Eric eSchadt Sean eBuchanan Kristen eBrennand Kalpana eMerchant |
| author_sort | Eric eSchadt |
| collection | DOAJ |
| description | A disruptive approach to therapeutic discovery and development is required in order to significantly improve the success rate of drug discovery for central nervous system (CNS) disorders. In this review, we first assess the key factors contributing to the frequent clinical failures for novel drugs. Second, we discuss cancer translational research paradigms that addressed key issues in drug discovery and development and have resulted in delivering drugs with significantly improved outcomes for patients. Finally, we discuss two emerging technologies that could improve the success rate of CNS therapies: human induced pluripotent stem cell (hiPSC)-based studies and multiscale biology models. Coincident with advances in cellular technologies that enable the generation of hiPSCs directly from patient blood or skin cells, together with methods to differentiate these hiPSC lines into specific neural cell types relevant to neurological disease, it is also now possible to combine data from large-scale forward genetics and post-mortem global epigenetic and expression studies in order to generate novel predictive models. The application of systems biology approaches to account for the multiscale nature of different data types, from genetic to molecular and cellular to clinical, can lead to new insights into human diseases that are emergent properties of biological networks, not the result of changes to single genes. Such studies have demonstrated the heterogeneity in etiological pathways and the need for studies on model systems that are patient-derived and thereby recapitulate neurological disease pathways with higher fidelity. In the context of two common and presumably representative neurological diseases, the neurodegenerative disease Alzheimer’s Disease (AD), and the psychiatric disorder schizophrenia (SZ), we propose the need for, and exemplify the impact of, a multiscale biology approach that can integrate panomic, clinical, imaging, and literature data in order to co |
| first_indexed | 2024-12-22T12:35:49Z |
| format | Article |
| id | doaj.art-f5184acd970c406f9684bed67a9039eb |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-22T12:35:49Z |
| publishDate | 2014-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-f5184acd970c406f9684bed67a9039eb2022-12-21T18:25:35ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122014-12-01510.3389/fphar.2014.00252112850Evolving towards a human-cell based and multiscale approach to drug discovery for CNS disordersEric eSchadt0Sean eBuchanan1Kristen eBrennand2Kalpana eMerchant3Icahn School of Medicine at Mount SinaiEli Lilly & CoIcahn School of Medicine at Mount SinaiIndependent consultantA disruptive approach to therapeutic discovery and development is required in order to significantly improve the success rate of drug discovery for central nervous system (CNS) disorders. In this review, we first assess the key factors contributing to the frequent clinical failures for novel drugs. Second, we discuss cancer translational research paradigms that addressed key issues in drug discovery and development and have resulted in delivering drugs with significantly improved outcomes for patients. Finally, we discuss two emerging technologies that could improve the success rate of CNS therapies: human induced pluripotent stem cell (hiPSC)-based studies and multiscale biology models. Coincident with advances in cellular technologies that enable the generation of hiPSCs directly from patient blood or skin cells, together with methods to differentiate these hiPSC lines into specific neural cell types relevant to neurological disease, it is also now possible to combine data from large-scale forward genetics and post-mortem global epigenetic and expression studies in order to generate novel predictive models. The application of systems biology approaches to account for the multiscale nature of different data types, from genetic to molecular and cellular to clinical, can lead to new insights into human diseases that are emergent properties of biological networks, not the result of changes to single genes. Such studies have demonstrated the heterogeneity in etiological pathways and the need for studies on model systems that are patient-derived and thereby recapitulate neurological disease pathways with higher fidelity. In the context of two common and presumably representative neurological diseases, the neurodegenerative disease Alzheimer’s Disease (AD), and the psychiatric disorder schizophrenia (SZ), we propose the need for, and exemplify the impact of, a multiscale biology approach that can integrate panomic, clinical, imaging, and literature data in order to cohttp://journal.frontiersin.org/Journal/10.3389/fphar.2014.00252/fullhigh throughput biologysystems biology and network biologyDrug Discovery Screeningcomplex disease mechanismstem cell based screening |
| spellingShingle | Eric eSchadt Sean eBuchanan Kristen eBrennand Kalpana eMerchant Evolving towards a human-cell based and multiscale approach to drug discovery for CNS disorders Frontiers in Pharmacology high throughput biology systems biology and network biology Drug Discovery Screening complex disease mechanism stem cell based screening |
| title | Evolving towards a human-cell based and multiscale approach to drug discovery for CNS disorders |
| title_full | Evolving towards a human-cell based and multiscale approach to drug discovery for CNS disorders |
| title_fullStr | Evolving towards a human-cell based and multiscale approach to drug discovery for CNS disorders |
| title_full_unstemmed | Evolving towards a human-cell based and multiscale approach to drug discovery for CNS disorders |
| title_short | Evolving towards a human-cell based and multiscale approach to drug discovery for CNS disorders |
| title_sort | evolving towards a human cell based and multiscale approach to drug discovery for cns disorders |
| topic | high throughput biology systems biology and network biology Drug Discovery Screening complex disease mechanism stem cell based screening |
| url | http://journal.frontiersin.org/Journal/10.3389/fphar.2014.00252/full |
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