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Pluripotent stem cells in disease modelling and drug discovery

Key Points

  • Embryonic stem cells and induced pluripotent stem cells (PSCs) are increasingly used to model human disorders, as a substitute for limited animal models.

  • National and international initiatives are currently establishing repositories of human PSCs as models for human disorders.

  • A wide range of disorders has been successfully modelled using PSCs, including monogenic, chromosomal and complex disorders, epigenetic disorders, and disorders that appear early or late in life.

  • A number of criteria should be considered when approaching the modelling of human disease using PSCs. In this Review, we outline certain optimal or challenging characteristics affecting the selection of disorders to be modelled.

  • A disease model can be used to understand the mechanisms underlying the cellular, molecular and physiological phenotypes of the disease, as well as to develop new therapies to attenuate the disorder.

  • PSC-derived cells are currently used to screen potential drug therapies for many disorders. We provide examples of drug discovery for 25 neurological disorders.

  • Drugs identified using PSC disease models are already on their way to the clinic.

Abstract

Experimental modelling of human disorders enables the definition of the cellular and molecular mechanisms underlying diseases and the development of therapies for treating them. The availability of human pluripotent stem cells (PSCs), which are capable of self-renewal and have the potential to differentiate into virtually any cell type, can now help to overcome the limitations of animal models for certain disorders. The ability to model human diseases using cultured PSCs has revolutionized the ways in which we study monogenic, complex and epigenetic disorders, as well as early- and late-onset diseases. Several strategies are used to generate such disease models using either embryonic stem cells (ES cells) or patient-specific induced PSCs (iPSCs), creating new possibilities for the establishment of models and their use in drug screening.

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Figure 1: Strategies for generating disease models using human pluripotent stem cells (PSCs).
Figure 2: Drug development strategies using human induced pluripotent stem cells (iPSCs).
Figure 3: Evaluation of drug screening studies using patient-derived induced pluripotent stem cell (iPSC) models for neurological disorders.

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Acknowledgements

The authors thank Eran Meshorer for his assistance in composing the glossary terms. I.S. is supported by the Adams Fellowships Program for Doctoral Students, and N.B. is the Herbert Cohn Chair in Cancer Research. This work was partially supported by the Israel Science Foundation (grant no. 269/12), by the Rosetrees Trust and by the Azrieli Foundation.

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FURTHER INFORMATION

CIRM

Coriell Biorepository

ECACC

HiPSCi

StemBANCC

New York Stem Cell Foundataion (NYSCF)

Glossary

Aneuploidy

The occurrence of an aberrant number of chromosomes within a cell, including both chromosome additions and deletions.

Primary cell lines

Cultured cells derived directly from source tissues. Primary cells usually have a normal karyotype and a limited replicative potential unless immortalized.

Self-renewal

The ability of a cell to give rise to indefinite number of cells of the same type.

Monogenic disorders

Genetic diseases arising from a mutation in a single gene. Examples include cystic fibrosis (mutations in the CFTR gene) and Lesch–Nyhan disease (mutations in the HPRT1 gene).

Complex disorders

Genetic diseases arising from alterations in several genes or that have an unclear genetic basis. Examples include forms of Alzheimer disease and diabetes.

Early-onset

Describes a disease in which phenotypes appear as early as fetal development or early childhood. Examples include Patau syndrome and fragile X syndrome.

Late-onset

Describes a disease in which phenotypes appear in adulthood. Examples include Alzheimer disease and Parkinson disease.

Chromosomal disorders

Diseases arising from either the loss or addition of chromosomes or subchromosomal regions. Examples include Down syndrome (trisomy of chromosome 21) and Turner syndrome (monosomy of chromosome X).

Pre-implantation genetic diagnosis

(PGD). Genetic profiling mainly of mutations within disease-causing genes in pre-implantation embryos produced by IVF. PGD is used to identify diseased embryos of parents with a predisposition for a specific disease.

Pre-implantation genetic screening

(PGS). Screening for chromosomal aberrations in pre-implantation embryos produced by IVF. PGS is used to identify embryos with chromosomal disorders, most commonly in cases of advanced maternal age or in women with multiple previous miscarriages.

Non-integrative reprogramming methods

Techniques that do not involve the insertion and persistence of ectopic reprogramming-inducing DNA sequences within the genome.

Penetrance

The proportion of individuals with a specific genotype who express it at the phenotypic level.

Haplotypes

Groups of adjacent genes and/or alleles that are usually inherited as clusters.

Parental genomic imprinting

A process by which parent-specific epigenetic modifications occur differentially in maternally and paternally inherited alleles.

Imprinting disorders

Disorders that originate from the aberrant regulation of imprinted genes. Examples include Prader–Willi syndrome and Angelman syndrome.

Parthenogenetic development

The development of an embryo from an unfertilized oocyte.

Organoids

Miniature organ-like structures generated in culture. Organoids vary in their complexity, but they are usually composed of several cell types and recapitulate three-dimensional organ development.

High-throughput screening

(HTS). A drug discovery strategy involving the analysis of a large array of compounds, which are chosen in an unbiased fashion. The effects of each compound on an aberrant phenotype are evaluated simultaneously.

Candidate drug approach

A drug discovery strategy involving compounds that were previously shown to affect a specific pathway or phenotype and that are tested as potential therapies for a specific disease on the basis of this information.

Clinical trials

Studies that evaluate potential treatments on human subjects. These trials are tightly regulated, have strict requirements and are composed of typical phases, evaluating the safety and efficacy of the treatment.

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Avior, Y., Sagi, I. & Benvenisty, N. Pluripotent stem cells in disease modelling and drug discovery. Nat Rev Mol Cell Biol 17, 170–182 (2016). https://doi.org/10.1038/nrm.2015.27

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