Dataset Information

Pharmacogenomic discovery using cell-based models.

ABSTRACT: Quantitative variation in response to drugs in human populations is multifactorial; genetic factors probably contribute to a significant extent. Identification of the genetic contribution to drug response typically comes from clinical observations and use of classic genetic tools. These clinical studies are limited by our inability to control environmental factors in vivo and the difficulty of manipulating the in vivo system to evaluate biological changes. Recent progress in dissecting genetic contribution to natural variation in drug response through the use of cell lines has been made and is the focus of this review. A general overview of current cell-based models used in pharmacogenomic discovery and validation is included. Discussion includes the current approach to translate findings generated from these cell-based models into the clinical arena and the use of cell lines for functional studies. Specific emphasis is given to recent advances emerging from cell line panels, including the International HapMap Project and the NCI60 cell panel. These panels provide a key resource of publicly available genotypic, expression, and phenotypic data while allowing researchers to generate their own data related to drug treatment to identify genetic variation of interest. Interindividual and interpopulation differences can be evaluated because human lymphoblastoid cell lines are available from major world populations of European, African, Chinese, and Japanese ancestry. The primary focus is recent progress in the pharmacogenomic discovery area through ex vivo models.

SUBMITTER: Welsh M

PROVIDER: S-EPMC2802425 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pharmacogenomic discovery using cell-based models.

Welsh Marleen M Mangravite Lara L Medina Marisa Wong MW Tantisira Kelan K Zhang Wei W Huang R Stephanie RS McLeod Howard H Dolan M Eileen ME

Pharmacological reviews 20091201 4

Quantitative variation in response to drugs in human populations is multifactorial; genetic factors probably contribute to a significant extent. Identification of the genetic contribution to drug response typically comes from clinical observations and use of classic genetic tools. These clinical studies are limited by our inability to control environmental factors in vivo and the difficulty of manipulating the in vivo system to evaluate biological changes. Recent progress in dissecting genetic c ...[more]

PMID: 20038569

Similar Datasets

Project description:Compelling clinical, social, and economic reasons exist to innovate in the process of drug discovery for neuropsychiatric disorders. The use of patient-specific, induced pluripotent stem cells (iPSCs) now affords the ability to generate neuronal cell-based models that recapitulate key aspects of human disease. In the context of neuropsychiatric disorders, where access to physiologically active and relevant cell types of the central nervous system for research is extremely limiting, iPSC-derived in vitro culture of human neurons and glial cells is transformative. Potential applications relevant to early stage drug discovery, include support of quantitative biochemistry, functional genomics, proteomics, and perhaps most notably, high-throughput and high-content chemical screening. While many phenotypes in human iPSC-derived culture systems may prove adaptable to screening formats, addressing the question of which in vitro phenotypes are ultimately relevant to disease pathophysiology and therefore more likely to yield effective pharmacological agents that are disease-modifying treatments requires careful consideration. Here, we review recent examples of studies of neuropsychiatric disorders using human stem cell models where cellular phenotypes linked to disease and functional assays have been reported. We also highlight technical advances using genome-editing technologies in iPSCs to support drug discovery efforts, including the interpretation of the functional significance of rare genetic variants of unknown significance and for the purpose of creating cell type- and pathway-selective functional reporter assays. Additionally, we evaluate the potential of in vitro stem cell models to investigate early events of disease pathogenesis, in an effort to understand the underlying molecular mechanism, including the basis of selective cell-type vulnerability, and the potential to create new cell-based diagnostics to aid in the classification of patients and subsequent selection for clinical trials. A number of key challenges remain, including the scaling of iPSC models to larger cohorts and integration with rich clinicopathological information and translation of phenotypes. Still, the overall use of iPSC-based human cell models with functional cellular and biochemical assays holds promise for supporting the discovery of next-generation neuropharmacological agents for the treatment and ultimately prevention of a range of severe mental illnesses.

Dataset Information

Pharmacogenomic discovery using cell-based models.

Publications

Pharmacogenomic discovery using cell-based models.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets