Editing the genome of hiPSC with CRISPR/Cas9: disease models.

paper Cited Public

Authors: Bassett, Andrew R
Year: 2017
Journal: Mammalian genome : official journal of the International Mammalian Genome Society
PMID: 28303292
DOI: 10.1007/s00335-017-9684-9
PMCID: PMC5569153

Fig. 1

Application of iPS models of disease to high throughput screening. Cells derived from patients with disease and healthy controls can be used to generate disease-relevant cell types, which can be phenotypically compared with each other. Such cells can be generated in sufficient numbers to be able to perform whole genome genetic screens to identify molecular and cellular mechanisms of disease and therapeutic targets, and also for high throughput drug screening to identify compounds that may be able to revert the disease phenotype. Differences between patient-derived and control cells can be used to identify potential therapeutic targets or agents

Fig. 2

Importance of genome editing in iPS disease modelling. iPSCs can be derived from healthy (blue) and disease (orange) patients, and after differentiation into an appropriate cell type, comparison of molecular or cellular phenotypes can be made. To minimise variability due to genetic background, genome editing can be used to either correct patient-derived cells (dark blue) or to introduce putative causative lesions into cells derived from healthy individuals (purple). This leads to isogenic pairs of cell lines (purple box or orange box) that identify the true impact of the engineered change on the cellular phenotype

Fig. 3

Linkage disequilibrium (LD) makes identification of causative SNPs challenging. In a typical region of the human genome, many SNPs (orange box) are in strong LD with the tag SNP (red) identified by a GWAS study. Genome editing can be used to identify the causative lesion from within this LD block. LD is measured as R-squared values between pairs of SNPs, and indicated on the heatmap

Fig. 4

Strategies for genome editing using CRISPR/Cas9. a Gene knockout—CRISPR-enhanced HDR can be employed to replace a critical exon with a selectable drug resistance cassette (drug R), on one allele, relying on NHEJ-dependent indels to disrupt the other allele. b Gene knockout—A CRISPR-induced DSB can be used to efficiently introduce indels on both alleles. c Conditional knockout by inversion (COIN)—CRISPR-enhanced HDR can be used to introduce a Cre-recombinase invertible cassette, flanked by loxP sites (black triangles) into an artificial intron. This contains a splice acceptor site followed by a transcriptional termination signal (pA), so in one orientation it causes premature termination and mutation of the gene. In the opposite orientation, splicing occurs around the cassette, allowing the normal gene product to be produced from this allele. The second allele is disrupted by NHEJ-induced indels as in (a). d SNP introduction—A CRISPR-induced DSB is used to enhance HDR with a 100–200 nt ssDNA oligonucleotide repair template (green) to introduce small defined changes. e Scarless SNP introduction—A selectable marker cassette (drug R, green) is introduced into an intron or non-functional region along with the SNP of interest, and subsequently removed by a further round of HDR, or the piggyBac transposase. f Scarless SNP introduction—A SNP of interest is introduced as in D along with second site mutations necessary to prevent re-cleavage by the Cas9 enzyme. A subsequent second round of editing in a similar manner corrects the secondary mutations to leave only the SNP of interest. g Epigenetic editing—Catalytically dead Cas9 protein is used to recruit a variety of enzymatic activities (Enz, green circle) to specific sites, leading to transcriptional modulation (both positively and negatively), DNA or histone modifications such as DNA methylation, histone acetylation, methylation or phosphorylation, or cytosine deamination

#	Section	Preview
0	Introduction — Current genetic models of disease	Thousands of human diseases are known to have a genetic component, although the penetrance of this…
1	Introduction — Current genetic models of disease	The evolutionary conservation of mammalian genomes, especially in protein coding sequence, has…
2	Introduction — Current genetic models of disease	2013). Equally, even apparently orthologous genes can play different roles, such as in the case of…
3	Introduction — Current genetic models of disease	One of the surprises of the human genome project (Lander et al. 2001) was that only a relatively…
4	Introduction — Current genetic models of disease	neighbouring gene expression (Degner et al. 2012). It is also beginning to become apparent that such…
5	Introduction — Current genetic models of disease	Primary cell cultures from human patients are an invaluable resource to study the molecular and…
6	Introduction — Current genetic models of disease	The generation of human embryonic stem cell (hESC) lines (Shamblott et al. 1998; Thomson et al.…
7	Induced pluripotent stem cells (iPSCs) for disease modelling — iPSC technology	The advent of induced pluripotent stem cell (iPSC) technology (Takahashi et al. 2007; Takahashi and…
8	Induced pluripotent stem cells (iPSCs) for disease modelling — iPSC technology	cells to be produced for high throughput genetic and drug screening as well as cell therapy. This…
9	Induced pluripotent stem cells (iPSCs) for disease modelling — iPSC technology	models of disease, and understand the molecular and cellular phenotypes underlying their…
10	Induced pluripotent stem cells (iPSCs) for disease modelling — Considerations for iPSC disease models	When considering use of iPSCs as a disease model, there are many important considerations; whether…
11	Induced pluripotent stem cells (iPSCs) for disease modelling — Considerations for iPSC disease models	Whilst the majority of genetic diseases are due to a small contribution from a large number of…
12	Induced pluripotent stem cells (iPSCs) for disease modelling — Considerations for iPSC disease models	Equally, it is critical with any iPSC disease model to pinpoint a cell type in which the disease…
13	Induced pluripotent stem cells (iPSCs) for disease modelling — Considerations for iPSC disease models	is the identification of a molecular or cellular phenotype that correlates with the disease state.…
14	Induced pluripotent stem cells (iPSCs) for disease modelling — Considerations for iPSC disease models	Another important consideration with the use of iPSCs in disease modelling is that these cells and…
15	Induced pluripotent stem cells (iPSCs) for disease modelling — Considerations for iPSC disease models	al. 2011). iPSC-derived dopaminergic neurons derived from these patients show molecular phenotypes…
16	Induced pluripotent stem cells (iPSCs) for disease modelling — Considerations for iPSC disease models	Importantly, it is perhaps unsurprising that even with late-onset diseases, there are pathogenic…
17	Induced pluripotent stem cells (iPSCs) for disease modelling — Limitations and developments	Whilst the benefits of iPSC technology are undeniable, there are some limitations in their use for…
18	Induced pluripotent stem cells (iPSCs) for disease modelling — Limitations and developments	Exciting developments in terms of three-dimensional culture systems such as intestinal (Dekkers et…
19	Induced pluripotent stem cells (iPSCs) for disease modelling — Limitations and developments	In certain instances, diseases manifest as complex physiological or behavioural phenotypes, which…

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In this knowledge base

Title	Year	PMID
Genetics of Alcohol Use Disorder: A Role for Induced Pluripotent Stem Cells?	2018	29897633

External

Title	Authors	Journal	Year	Link
Advances and optimization strategies in prime editing of human pluripotent stem cells.	Getachew H et al.	—	2026	→
iPSC-Derived Endothelial Cells as Experimental Models for Predictive and Personalized Strategies in Cardiovascular and Cerebrovascular Disease.	Fontanelli L et al.	—	2026	→
Neuronal Organoid Engineering and Disease-Focused High-Throughput Neuropharmacology: Advances, Limitations, and Translational Strategies.	Farasati Far B et al.	—	2026	→
CRISPR Technology and Its Emerging Applications.	Zhang X et al.	—	2025	→
Current approaches in CRISPR-Cas system for metabolic disorder.	Arora Y et al.	—	2025	→
Engineering the next generation of allogeneic CAR cells: iPSCs as a scalable and editable platform.	Fang Y et al.	—	2025	→
Pluripotent Stem Cells: Recent Advances and Emerging Trends.	Wang AYL et al.	—	2025	→
Right ventricle remodelling: from <i>in vitro</i> to <i>in vivo</i> and from simple to complex models.	da Costa Martins PA et al.	—	2025	→
SOX9 haploinsufficiency reveals SOX9-Noggin interaction in BMP-SMAD signaling pathway in chondrogenesis.	Ha TY et al.	—	2025	→
Stem Cell-Based Approaches for Spinal Cord Injury: The Promise of iPSCs.	Zeng CW	—	2025	→
Compact CRISPR genetic screens enabled by improved guide RNA library cloning.	Heo SJ et al.	—	2024	→
Considerations for the development of iPSC-derived cell therapies: a review of key challenges by the JSRM-ISCT iPSC Committee.	Madrid M et al.	—	2024	→
Correction of I<sub>to</sub> in human induced pluripotent stem Cell-derived cardiomyocyte carrying DPP6 mutation in early repolarization syndrome by CRISPR/Cas9 genome editing.	Wu Y et al.	—	2024	→
Generation of an Isogenic Hereditary Hemorrhagic Telangiectasia Model via Prime Editing in Human Induced Pluripotent Stem Cells.	Kim MW et al.	—	2024	→
Genetic and Cellular Basis of Impaired Phagocytosis and Photoreceptor Degeneration in CLN3 Disease.	Han J et al.	—	2024	→
In vitro human cell culture models in a bench-to-bedside approach to epilepsy.	Danačíková Š et al.	—	2024	→
Modeling Choroideremia Disease with Isogenic Induced Pluripotent Stem Cells.	Fonseca AF et al.	—	2024	→
Mutations in DNAJC19 cause altered mitochondrial structure and increased mitochondrial respiration in human iPSC-derived cardiomyocytes.	Janz A et al.	—	2024	→
Parallelized engineering of mutational models using piggyBac transposon delivery of CRISPR libraries.	Nuttle X et al.	—	2024	→
Past, present, and future of CRISPR genome editing technologies.	Pacesa M et al.	—	2024	→
Patient-derived induced pluripotent stem cells: Tools to advance the understanding and drug discovery in Major Depressive Disorder.	Vaz A et al.	—	2024	→
Pleiotropy, epistasis and the genetic architecture of quantitative traits.	Mackay TFC et al.	—	2024	→
CRISPR/Cas9 and <i>piggyBac</i> Transposon-Based Conversion of a Pathogenic Biallelic <i>TBCD</i> Variant in a Patient-Derived iPSC Line Allows Correction of PEBAT-Related Endophenotypes.	Muto V et al.	—	2023	→
CRISPR-Cas9 correction of a nonsense mutation in <i>LCA5</i> rescues lebercilin expression and localization in human retinal organoids.	Afanasyeva TAV et al.	—	2023	→
Emerging trends in organ-on-a-chip systems for drug screening.	Wang Y et al.	—	2023	→
Functional genomics in stem cell models: considerations and applications.	Shevade K et al.	—	2023	→
High-Efficiency CRISPR/Cas9-Mediated Correction of a Homozygous Mutation in Achromatopsia-Patient-Derived iPSCs.	Siles L et al.	—	2023	→
On the utilization of the induced pluripotent stem cell (iPSC) model to study substance use disorders: A scoping review protocol.	Niemis W et al.	—	2023	→
Recommendations, guidelines, and best practice for the use of human induced pluripotent stem cells for neuropharmacological studies of neuropsychiatric disorders.	Dutan Polit L et al.	—	2023	→
Toward the use of novel alternative methods in epilepsy modeling and drug discovery.	Miguel Sanz C et al.	—	2023	→
An induced pluripotent stem cell-derived NMJ platform for study of the NGLY1-Congenital Disorder of Deglycosylation.	Sasserath T et al.	—	2022	→
Cortical Organoids to Model Microcephaly.	Farcy S et al.	—	2022	→
Gene Editing in Human Induced Pluripotent Stem Cells Using Doxycycline-Inducible CRISPR-Cas9 System.	Thamodaran V et al.	—	2022	→
Generation of Monoclonal iPSC Lines with Stable Cas9 Expression and High Cas9 Activity.	Liao JQ et al.	—	2022	→
Genome Editing and Human Pluripotent Stem Cell Technologies for in vitro Monogenic Diabetes Modeling.	Dabi YT et al.	—	2022	→
Human-Induced Pluripotent Stem Cell Technology: Toward the Future of Personalized Psychiatry.	Alciati A et al.	—	2022	→
Induced Pluripotent Stem Cells and Genome-Editing Tools in Determining Gene Function and Therapy for Inherited Retinal Disorders.	Benati D et al.	—	2022	→
MSCs vs. iPSCs: Potential in therapeutic applications.	Thanaskody K et al.	—	2022	→
Plumping up a Cushion of Human Biowaste in Regenerative Medicine: Novel Insights into a State-of-the-Art Reserve Arsenal.	Najafi-Ghalehlou N et al.	—	2022	→
Basic and Preclinical Research for Personalized Medicine.	Lattanzi W et al.	—	2021	→
Functional genomics of autoimmune diseases.	Suzuki A et al.	—	2021	→
Human Induced Pluripotent Stem Cell as a Disease Modeling and Drug Development Platform-A Cardiac Perspective.	Bekhite MM et al.	—	2021	→
Human neuronal networks on micro-electrode arrays are a highly robust tool to study disease-specific genotype-phenotype correlations<i>in vitro</i>	Mossink B et al.	—	2021	—
Targeting α-Synuclein in Parkinson's Disease by Induced Pluripotent Stem Cell Models.	Spathopoulou A et al.	—	2021	→
Aortic "Disease-in-a-Dish": Mechanistic Insights and Drug Development Using iPSC-Based Disease Modeling.	Davaapil H et al.	—	2020	→
Application of CRISPR/Cas9 to human-induced pluripotent stem cells: from gene editing to drug discovery.	De Masi C et al.	—	2020	→
Application of CRISPR Tools for Variant Interpretation and Disease Modeling in Inherited Retinal Dystrophies.	Fuster-García C et al.	—	2020	→
A roadmap for neurodevelopmental disease modeling for non-stem cell biologists.	Ernst C	—	2020	→
Comparisons of dual isogenic human iPSC pairs identify functional alterations directly caused by an epilepsy associated SCN1A mutation.	Xie Y et al.	—	2020	→
Copy number variants (CNVs): a powerful tool for iPSC-based modelling of ASD.	Drakulic D et al.	—	2020	→
CRISPR/Cas9 knock-in toward creating a Rett syndrome cell model with a synonymous mutation in the MECP2 gene.	Khalili Alashti S et al.	—	2020	→
Current biomarker-associated procedures of cancer modeling-a reference in the context of IDH1 mutant glioma.	Mehrjardi NZ et al.	—	2020	→
Disease modeling and stem cell immunoengineering in regenerative medicine using CRISPR/Cas9 systems.	Antao AM et al.	—	2020	→
Human pluripotent stem cell-derived models and drug screening in CNS precision medicine.	Silva MC et al.	—	2020	→
A decade in psychiatric GWAS research.	Horwitz T et al.	—	2019	→
Application of Urine-Derived Stem Cells to Cellular Modeling in Neuromuscular and Neurodegenerative Diseases.	Sato M et al.	—	2019	→
Considerations for an <i>In Vitro</i>, Cell-Based Testing Platform for Detection of Drug-Induced Inotropic Effects in Early Drug Development. Part 2: Designing and Fabricating Microsystems for Assaying Cardiac Contractility With Physiological Relevance Using Human iPSC-Cardiomyocytes.	Ribeiro AJS et al.	—	2019	→
CRISPR-Mediated Gene Editing: Scientific and Ethical Issues.	Bailey J	—	2019	→
Editing the Genome of Human Induced Pluripotent Stem Cells Using CRISPR/Cas9 Ribonucleoprotein Complexes.	Bruntraeger M et al.	—	2019	→
Functional Interrogation of a Depression-Related Serotonergic Single Nucleotide Polymorphism, rs6295, Using a Humanized Mouse Model.	Cunningham AM et al.	—	2019	→
Genome-Wide Association Studies of Endometrial Cancer: Latest Developments and Future Directions.	O'Mara TA et al.	—	2019	→
Human iPSCs-Derived Endothelial Cells with Mutation in <i>HNF1A</i> as a Model of Maturity-Onset Diabetes of the Young.	Kachamakova-Trojanowska N et al.	—	2019	→
Novel variants and phenotypes widen the phenotypic spectrum of GABRG2-related disorders.	Komulainen-Ebrahim J et al.	—	2019	→
CRISPR editing in biological and biomedical investigation.	Huang J et al.	—	2018	→
Disease Modeling Using 3D Organoids Derived from Human Induced Pluripotent Stem Cells.	Ho BX et al.	—	2018	→
Genetics of Alcohol Use Disorder: A Role for Induced Pluripotent Stem Cells?	Prytkova I et al.	—	2018	→
Genome Editing of Induced Pluripotent Stem Cells to Decipher Cardiac Channelopathy Variant.	Garg P et al.	—	2018	→
Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes as Models for Cardiac Channelopathies: A Primer for Non-Electrophysiologists.	Garg P et al.	—	2018	→
Patient-Derived Induced Pluripotent Stem Cells and Organoids for Modeling Alpha Synuclein Propagation in Parkinson's Disease.	Koh YH et al.	—	2018	→
Stem cell transplantation for Huntington's diseases.	Choi KA et al.	—	2018	→
Updated summary of genome editing technology in human cultured cells linked to human genetics studies.	Miyamoto T et al.	—	2018	→