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Manoubi W, Mahdouani M, Hmida D, Kdissa A, Rouissi A, Turki I, Gueddiche N, Soyah N, Saad A, Bouwkamp C, Elgersma Y, Mougou-Zerelli S, Gribaa M. Genetic investigation of the ubiquitin-protein ligase E3A gene as putative target in Angelman syndrome. World J Clin Cases 2024; 12:503-516. [PMID: 38322471 PMCID: PMC10841941 DOI: 10.12998/wjcc.v12.i3.503] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/12/2023] [Accepted: 01/04/2024] [Indexed: 01/18/2024] Open
Abstract
BACKGROUND Angelman syndrome (AS) is caused by maternal chromosomal deletions, imprinting defects, paternal uniparental disomy involving chromosome 15 and the ubiquitin-protein ligase UBE3A gene mutations. However the genetic basis remains unclear for several patients. AIM To investigate the involvement of UBE3A gene in AS and identifying new potential genes using exome sequencing. METHODS We established a cohort study in 50 patients referred to Farhat Hached University Hospital between 2006 and 2021, with a strong suspicion of AS and absence of chromosomal aberrations. The UBE3A gene was screened for mutation detection. Two unrelated patients issued from consanguineous families were subjected to exome analysis. RESULTS We describe seven UBE3A variants among them 3 none previously described including intronic variants c.2220+14T>C (intron14), c.2507+43T>A (Exon15) and insertion in Exon7: c.30-47_30-46. The exome sequencing revealed 22 potential genes that could be involved in AS-like syndromes that should be investigated further. CONCLUSION Screening for UBE3A mutations in AS patients has been proven to be useful to confirm the diagnosis. Our exome findings could rise to new potential alternative target genes for genetic counseling.
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Affiliation(s)
- Wiem Manoubi
- Laboratory of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat Hached University Hospital, Sousse 4000, Tunisia
- Higher Institute of Biotechnology of Monastir, University of Monastir, Monastir 3000, Tunisia
| | - Marwa Mahdouani
- Laboratory of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat Hached University Hospital, Sousse 4000, Tunisia
- Higher Institute of Biotechnology of Monastir, University of Monastir, Monastir 3000, Tunisia
| | - Dorra Hmida
- Laboratory of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat Hached University Hospital, Sousse 4000, Tunisia
| | - Ameni Kdissa
- Laboratory of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat Hached University Hospital, Sousse 4000, Tunisia
| | - Aida Rouissi
- Department of Neuropediatry, La Rabta Hospital, Tunis 2000, Tunisia
| | - Ilhem Turki
- Department of Neuropediatry, La Rabta Hospital, Tunis 2000, Tunisia
| | - Neji Gueddiche
- Department of Pediatric, Fattouma Bourguiba Hospital Monastir, Monastir 2003, Tunisia
| | - Najla Soyah
- Department of Pediatric, Farhat Hached University Hospital, Sousse 4000, Tunisia
| | - Ali Saad
- Laboratory of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat Hached University Hospital, Sousse 4000, Tunisia
| | - Christian Bouwkamp
- Department of Neuroscience, Erasmus MC, the Netherlands, Rotterdam 3112 td, Netherlands
| | - Ype Elgersma
- Department of Neuroscience, Erasmus MC, the Netherlands, Rotterdam 3112 td, Netherlands
| | - Soumaya Mougou-Zerelli
- Laboratory of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat Hached University Hospital, Sousse 4000, Tunisia
| | - Moez Gribaa
- Laboratory of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat Hached University Hospital, Sousse 4000, Tunisia
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Calvert BA, Ryan Firth AL. Application of iPSC to Modelling of Respiratory Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1237:1-16. [PMID: 31468358 PMCID: PMC8274633 DOI: 10.1007/5584_2019_430] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Respiratory disease is one of the leading causes of morbidity and mortality world-wide with an increasing incidence as the aged population prevails. Many lung diseases are treated for symptomatic relief, with no cure available, indicating a critical need for novel therapeutic strategies. Such advances are hampered by a lack of understanding of how human lung pathologies initiate and progress. Research on human lung disease relies on the isolation of primary cells from explanted lungs or the use of immortalized cells, both are limited in their capacity to represent the genomic and phenotypic variability among the population. In an era where we are progressing toward precision medicine the use of patient specific induced pluripotent cells (iPSC) to generate models, where sufficient primary cells and tissues are scarce, has increased our capacity to understand human lung pathophysiology. Directed differentiation of iPSC toward lung presented the initial challenge to overcome in generating iPSC-derived lung epithelial cells. Since then major advances have been made in defining protocols to specify and isolate specific lung lineages, with the generation of airway spheroids and multi cellular organoids now possible. This technological advance has opened up our capacity for human lung research and prospects for autologous cell therapy. This chapter will focus on the application of iPSC to studying human lung disease.
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Affiliation(s)
- Ben A Calvert
- Hastings Center for Pulmonary Research, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Amy L Ryan Firth
- Hastings Center for Pulmonary Research, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Southern California, Los Angeles, CA, USA.
- Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, CA, USA.
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Wang H. Modeling Neurological Diseases With Human Brain Organoids. Front Synaptic Neurosci 2018; 10:15. [PMID: 29937727 PMCID: PMC6002496 DOI: 10.3389/fnsyn.2018.00015] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Accepted: 05/22/2018] [Indexed: 12/18/2022] Open
Abstract
The complexity and delicacy of human brain make it challenging to recapitulate its development, function and disorders. Brain organoids derived from human pluripotent stem cells (PSCs) provide a new tool to model both normal and pathological human brain, and greatly enhance our ability to study brain biology and diseases. Currently, human brain organoids are increasingly used in modeling neurological disorders and relative therapeutic discovery. This review article focuses on recent advances in human brain organoid system and its application in disease modeling. It also discusses the limitations and future perspective of human brain organoids in modeling neurological diseases.
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Affiliation(s)
- Hansen Wang
- Faculty of Medicine, University of Toronto, Toronto, ON, Canada
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Abstract
UNLABELLED Fragile X syndrome (FXS), the most common form of inherited mental retardation, is a neurodevelopmental disorder caused by silencing of the FMR1 gene, which in FXS becomes inactivated during human embryonic development. We have shown recently that this process is recapitulated by in vitro neural differentiation of FX human embryonic stem cells (FX-hESCs), derived from FXS blastocysts. In the present study, we analyzed morphological and functional properties of neurons generated from FX-hESCs. Human FX neurons can fire single action potentials (APs) to depolarizing current commands, but are unable to discharge trains of APs. Their APs are of a reduced amplitudes and longer durations than controls. These are reflected in reduced inward Na(+) and outward K(+) currents. In addition, human FX neurons contain fewer synaptic vesicles and lack spontaneous synaptic activity. Notably, synaptic activity in these neurons can be restored by coculturing them with normal rat hippocampal neurons, demonstrating a critical role for synaptic mechanisms in FXS pathology. This is the first extensive functional analysis of human FX neurons derived in vitro from hESCs that provides a convenient tool for studying molecular mechanisms underlying the impaired neuronal functions in FXS. SIGNIFICANCE STATEMENT Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by silencing of the FMR1 gene. In this study, we describe for the first time the properties of neurons developed from human embryonic stem cells (hESCs) that carry the FMR1 mutation and are grown in culture for extended periods. These neurons are retarded compared with controls in several morphological and functional properties. In vitro neural differentiation of FX hESCs can thus serve as a most relevant system for the analysis of molecular mechanisms underlying the impaired neuronal functions in FXS.
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Abstract
Cardiovascular and neurodegenerative diseases are major health threats in many
developed countries. Recently, target tissues derived from human embryonic stem
(hES) cells and induced pluripotent stem cells (iPSCs), such as cardiomyocytes
(CMs) or neurons, have been actively mobilized for drug screening. Knowledge of
drug toxicity and efficacy obtained using stem cell-derived tissues could
parallel that obtained from human trials. Furthermore, iPSC disease models could
be advantageous in the development of personalized medicine in various parts of
disease sectors. To obtain the maximum benefit from iPSCs in disease modeling,
researchers are now focusing on aging, maturation, and metabolism to
recapitulate the pathological features seen in patients. Compared to pediatric
disease modeling, adult-onset disease modeling with iPSCs requires proper
maturation for full manifestation of pathological features. Herein, the success
of iPSC technology, focusing on patient-specific drug treatment,
maturation-based disease modeling, and alternative approaches to compensate for
the current limitations of patient iPSC modeling, will be further discussed.
[BMB Reports 2015; 48(5): 256-265]
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Affiliation(s)
- Changsung Kim
- Department of Bioscience and Biotechnology, Sejong University, Seoul 143-747, Korea
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6
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Wang H, Doering LC. Autism spectrum disorders: emerging mechanisms and mechanism-based treatment. Front Cell Neurosci 2015; 9:183. [PMID: 26029053 PMCID: PMC4428121 DOI: 10.3389/fncel.2015.00183] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 04/27/2015] [Indexed: 12/27/2022] Open
Affiliation(s)
- Hansen Wang
- Faculty of Medicine, University of Toronto Toronto, ON, Canada
| | - Laurie C Doering
- Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University Hamilton, ON, Canada
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Telias M, Ben-Yosef D. Modeling neurodevelopmental disorders using human pluripotent stem cells. Stem Cell Rev Rep 2015; 10:494-511. [PMID: 24728983 DOI: 10.1007/s12015-014-9507-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Neurodevelopmental disorders (NDs) are impairments that affect the development and growth of the brain and the central nervous system during embryonic and early postnatal life. Genetically manipulated animals have contributed greatly to the advancement of ND research, but many of them differ considerably from the human phenotype. Cellular in vitro models are also valuable, but the availability of human neuronal cells is limited and their lifespan in culture is short. Human pluripotent stem cells (hPSCs), including embryonic stem cells and induced pluripotent stem cells, comprise a powerful tool for studying developmentally regulated diseases, including NDs. We reviewed all recent studies in which hPSCs were used as in vitro models for diseases and syndromes characterized by impairment of neurogenesis or synaptogenesis leading to intellectual disability and delayed neurodevelopment. We analyzed their methodology and results, focusing on the data obtained following in vitro neural differentiation and gene expression and profiling of the derived neurons. Electrophysiological recording of action potentials, synaptic currents and response to neurotransmitters is pivotal for validation of the neuronal fate as well as for assessing phenotypic dysfunctions linked to the disease in question. We therefore focused on the studies which included electrophysiological recordings on the in vitro-derived neurons. Finally, we addressed specific issues that are critical for the advancement of this area of research, specifically in providing a reliable human pre-clinical research model and drug screening platform.
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Affiliation(s)
- Michael Telias
- The Wolfe PGD-Stem Cell Lab, Racine IVF Unit, Lis Maternity Hospital, Tel-Aviv Sourasky Medical Center, Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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Wang H, Pati S, Pozzo-Miller L, Doering LC. Targeted pharmacological treatment of autism spectrum disorders: fragile X and Rett syndromes. Front Cell Neurosci 2015; 9:55. [PMID: 25767435 PMCID: PMC4341567 DOI: 10.3389/fncel.2015.00055] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2015] [Accepted: 02/05/2015] [Indexed: 12/27/2022] Open
Abstract
Autism spectrum disorders (ASDs) are genetically and clinically heterogeneous and lack effective medications to treat their core symptoms. Studies of syndromic ASDs caused by single gene mutations have provided insights into the pathophysiology of autism. Fragile X and Rett syndromes belong to the syndromic ASDs in which preclinical studies have identified rational targets for drug therapies focused on correcting underlying neural dysfunction. These preclinical discoveries are increasingly translating into exciting human clinical trials. Since there are significant molecular and neurobiological overlaps among ASDs, targeted treatments developed for fragile X and Rett syndromes may be helpful for autism of different etiologies. Here, we review the targeted pharmacological treatment of fragile X and Rett syndromes and discuss related issues in both preclinical studies and clinical trials of potential therapies for the diseases.
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Affiliation(s)
- Hansen Wang
- Faculty of Medicine, University of Toronto, 1 King's College Circle Toronto, ON, Canada
| | - Sandipan Pati
- Department of Neurology, Epilepsy Division, The University of Alabama at Birmingham Birmingham, AL, USA
| | - Lucas Pozzo-Miller
- Department of Neurobiology, Civitan International Research Center, The University of Alabama at Birmingham Birmingham, AL, USA
| | - Laurie C Doering
- Faculty of Health Sciences, Department of Pathology and Molecular Medicine, McMaster University Hamilton, ON, Canada
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Reisman M, Adams KT. Stem cell therapy: a look at current research, regulations, and remaining hurdles. P & T : A PEER-REVIEWED JOURNAL FOR FORMULARY MANAGEMENT 2014; 39:846-857. [PMID: 25516694 PMCID: PMC4264671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Stem cell therapies offer great promise for a wide range of diseases and conditions. However, stem cell research-particularly human embryonic stem cell research-has also been a source of ongoing ethical, religious, and political controversy.
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Kim C, Lee HC, Sung JJ. Amyotrophic lateral sclerosis - cell based therapy and novel therapeutic development. Exp Neurobiol 2014; 23:207-14. [PMID: 25258567 PMCID: PMC4174611 DOI: 10.5607/en.2014.23.3.207] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Revised: 08/27/2014] [Accepted: 08/27/2014] [Indexed: 12/13/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, characterized by the predominant loss of motor neurons (MNs) in primary motor cortex, the brainstem, and the spinal cord, causing premature death in most cases. Minimal delay of pathological development by available medicine has prompted the search for novel therapeutic treatments to cure ALS. Cell-based therapy has been proposed as an ultimate source for regeneration of MNs. Recent completion of non-autologous fetal spinal stem cell transplant to ALS patients brought renewed hope for further human trials to cure the disease. Autologous somatic stem cell-based human trials are now in track to reveal the outcome of the ongoing trials. Furthermore, induced pluripotent stem cell (iPSC)-based ALS disease drug screen and autologous cell transplant options will broaden therapeutic options. In this review paper, we discuss recent accomplishments in cell transplant treatment for ALS and future options with iPSC technology.
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Affiliation(s)
- Changsung Kim
- Department of Bioscience and Biotechnology, Sejong University, Seoul 143-747, Korea
| | - Hee Chul Lee
- Department of Bioscience and Biotechnology, Sejong University, Seoul 143-747, Korea
| | - Jung-Joon Sung
- Department of Neurology, Seoul National University Hospital, Seoul 110-774, Korea
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11
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Ferrer M, Corneo B, Davis J, Wan Q, Miyagishima KJ, King R, Maminishkis A, Marugan J, Sharma R, Shure M, Temple S, Miller S, Bharti K. A multiplex high-throughput gene expression assay to simultaneously detect disease and functional markers in induced pluripotent stem cell-derived retinal pigment epithelium. Stem Cells Transl Med 2014; 3:911-22. [PMID: 24873859 DOI: 10.5966/sctm.2013-0192] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
There is continuing interest in the development of lineage-specific cells from induced pluripotent stem (iPS) cells for use in cell therapies and drug discovery. Although in most cases differentiated cells show features of the desired lineage, they retain fetal gene expression and do not fully mature into "adult-like" cells. Such cells may not serve as an effective therapy because, once implanted, immature cells pose the risk of uncontrolled growth. Therefore, there is a need to optimize lineage-specific stem cell differentiation protocols to produce cells that no longer express fetal genes and have attained "adult-like" phenotypes. Toward that goal, it is critical to develop assays that simultaneously measure cell function and disease markers in high-throughput format. Here, we use a multiplex high-throughput gene expression assay that simultaneously detects endogenous expression of multiple developmental, functional, and disease markers in iPS cell-derived retinal pigment epithelium (RPE). We optimized protocols to differentiate iPS cell-derived RPE that was then grown in 96- and 384-well plates. As a proof of principle, we demonstrate differential expression of eight genes in iPS cells, iPS cell-derived RPE at two different differentiation stages, and primary human RPE using this multiplex assay. The data obtained from the multiplex gene expression assay are significantly correlated with standard quantitative reverse transcription-polymerase chain reaction-based measurements, confirming the ability of this high-throughput assay to measure relevant gene expression changes. This assay provides the basis to screen for compounds that improve RPE function and maturation and target disease pathways, thus providing the basis for effective treatments of several retinal degenerative diseases.
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Affiliation(s)
- Marc Ferrer
- NIH Center for Advancing Translational Sciences, NIH, Bethesda, MD, USA
| | - Barbara Corneo
- Neural Stem Cell Institute, Rennselaer, New York, NY, USA
| | - Janine Davis
- Unit on Ocular and Stem Cell Translational Research, National Eye Institute, NIH, Bethesda, MD, USA
| | - Qin Wan
- Section on Epithelial and Retinal Physiology and Disease, National Eye Institute, NIH, Bethesda, MD, USA
| | | | - Rebecca King
- NIH Center for Advancing Translational Sciences, NIH, Bethesda, MD, USA
| | - Arvydas Maminishkis
- Section on Epithelial and Retinal Physiology and Disease, National Eye Institute, NIH, Bethesda, MD, USA
| | - Juan Marugan
- NIH Center for Advancing Translational Sciences, NIH, Bethesda, MD, USA
| | - Ruchi Sharma
- Unit on Ocular and Stem Cell Translational Research, National Eye Institute, NIH, Bethesda, MD, USA
| | | | - Sally Temple
- Neural Stem Cell Institute, Rensselaer, New York, NY, USA
| | - Sheldon Miller
- Section on Epithelial and Retinal Physiology, National Eye Institute, NIH, Bethesda, MD, USA
| | - Kapil Bharti
- Unit on Ocular and Stem Cell Translational Research, National Eye Institute, Bethesda, MD, USA.
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Guerra M. Neural stem cells: are they the hope of a better life for patients with fetal-onset hydrocephalus? Fluids Barriers CNS 2014; 11:7. [PMID: 24685106 PMCID: PMC4002203 DOI: 10.1186/2045-8118-11-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Accepted: 03/26/2014] [Indexed: 01/01/2023] Open
Abstract
I was honored to be awarded the Casey Holter Essay Prize in 2013 by the Society for Research into Hydrocephalus and Spina Bifida. The purpose of the prize is to encourage original thinking in a way to improve the care of individuals with spina bifida and hydrocephalus. Having kept this purpose in mind, I have chosen the title: Neural stem cells, are they the hope of a better life for patients with fetal-onset hydrocephalus? The aim is to review and discuss some of the most recent and relevant findings regarding mechanisms leading to both hydrocephalus and abnormal neuro/gliogenesis. By looking at these outcome studies, it is hoped that we will recognize the potential use of neural stem cells in the treatment of hydrocephalus, and so prevent the disease or diminish/repair the associated brain damage.
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Affiliation(s)
- Montserrat Guerra
- Instituto de Anatomía, Histología y Patología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
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Kim C. Disease modeling and cell based therapy with iPSC: future therapeutic option with fast and safe application. Blood Res 2014; 49:7-14. [PMID: 24724061 PMCID: PMC3974965 DOI: 10.5045/br.2014.49.1.7] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 03/18/2014] [Accepted: 03/19/2014] [Indexed: 12/20/2022] Open
Abstract
Induced pluripotent stem cell (iPSC) technology has shown us great hope to treat various human diseases which have been known as untreatable and further endows personalized medicine for future therapy without ethical issues and immunological rejection which embryonic stem cell (hES) treatment has faced. It has been agreed that iPSCs knowledge can be harnessed from disease modeling which mimics human pathological development rather than trials utilizing conventional rodent and cell lines. Now, we can routinely generate iPSC from patient specific cell sources, such as skin fibroblast, hair follicle cells, patient blood samples and even urine containing small amount of epithelial cells. iPSC has both similarity and dissimilarity to hES. iPSC is similar enough to regenerate tissue and even full organism as ES does, however what we want for therapeutic advantage is limited to regenerated tissue and lineage specific differentiation. Depending on the lineage and type of cells, both tissue memory containing (DNA rearrangement/epigenetics) and non-containing iPSC can be generated. This makes iPSC even better choice to perform disease modeling as well as cell based therapy. Tissue memory containing iPSC from mature leukocytes would be beneficial for curing cancer and infectious disease. In this review, the benefit of iPSC for translational approaches will be presented.
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Affiliation(s)
- Changsung Kim
- Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea
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Disease modeling and drug screening for neurological diseases using human induced pluripotent stem cells. Acta Pharmacol Sin 2013; 34:755-64. [PMID: 23685955 PMCID: PMC3674515 DOI: 10.1038/aps.2013.63] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
With the general decline of pharmaceutical research productivity, there are concerns that many components of the drug discovery process need to be redesigned and optimized. For example, the human immortalized cell lines or animal primary cells commonly used in traditional drug screening may not faithfully recapitulate the pathological mechanisms of human diseases, leading to biases in assays, targets, or compounds that do not effectively address disease mechanisms. Recent advances in stem cell research, especially in the development of induced pluripotent stem cell (iPSC) technology, provide a new paradigm for drug screening by permitting the use of human cells with the same genetic makeup as the patients without the typical quantity constraints associated with patient primary cells. In this article, we will review the progress made to date on cellular disease models using human stem cells, with a focus on patient-specific iPSCs for neurological diseases. We will discuss the key challenges and the factors that associated with the success of using stem cell models for drug discovery through examples from monogenic diseases, diseases with various known genetic components, and complex diseases caused by a combination of genetic, environmental and other factors.
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