Genome-Editing Technologies: Principles and Applications

Gaj, Thomas; Sirk, Shannon J.; Shui, Sai Lan; Liu, Jia

doi:10.1101/cshperspect.a023754

Cited by 297 publications

(166 citation statements)

References 259 publications

(238 reference statements)

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“…Endogenous gene network repurposing becomes now possible with the recent advances of gene editing technics 66 and DNA template vectorization methods (single and double DNA templates 31,34,[67][68][69] , and AAV6-embeded template 26,29,32,70 ). Our work illustrates the therapeutic potential of this approach by rewiring different elements of the TCR activation pathway, but is not limited to it.…”

Section: Discussionmentioning

confidence: 99%

Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality

et al. 2019

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Endowing chimeric antigen receptor (CAR) T cells with additional potent functionalities holds strong potential for improving their antitumor activity. However, because potency could be deleterious without control, these additional features need to be tightly regulated. Immune pathways offer a wide array of tightly regulated genes that can be repurposed to express potent functionalities in a highly controlled manner. Here, we explore this concept by repurposing TCR, CD25 and PD1, three major players of the T cell activation pathway. We insert the CAR into the TCRα gene (TRAC CAR), and IL-12P70 into either IL2Rα or PDCD1 genes. This process results in transient, antigen concentration-dependent IL-12P70 secretion, increases TRAC CAR T cell cytotoxicity and extends survival of tumor-bearing mice. This gene network repurposing strategy can be extended to other cellular pathways, thus paving the way for generating smart CAR T cells able to integrate biological inputs and to translate them into therapeutic outputs in a highly regulated manner.

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Section: Discussionmentioning

confidence: 99%

Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality

et al. 2019

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“…Nonetheless, the actual function of the changed proteins resulting from the DNA sequence variants still needs verification. Gene knockouts using genome editing technologies (Gaj et al 2016), as well as gene expression analysis (Lovén et al 2012), could verify the involvement of the sequence variants and associated genes in seed storage protein metabolic pathways in pigeonpea. In addition, it is possible that other types of causative sequence variants have been overlooked in the panel of selected genes as a result of the strategies used to prioritize the candidate variants.…”

Section: Discussionmentioning

confidence: 99%

Development of sequence-based markers for seed protein content in pigeonpea

et al. 2018

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Pigeonpea is an important source of dietary protein to over a billion people globally, but genetic enhancement of seed protein content (SPC) in the crop has received limited attention for a long time. Use of genomics-assisted breeding would facilitate accelerating genetic gain for SPC. However, neither genetic markers nor genes associated with this important trait have been identified in this crop. Therefore, the present study exploited whole genome re-sequencing (WGRS) data of four pigeonpea genotypes (~ 12X coverage) to identify sequence-based markers and associated candidate genes for SPC. By combining a common variant filtering strategy on available WGRS data with knowledge of gene functions in relation to SPC, 108 sequence variants from 57 genes were identified. These genes were assigned to 19 GO molecular function categories with 56% belonging to only two categories. Furthermore, Sanger sequencing confirmed presence of 75.4% of the variants in 37 genes. Out of 30 sequence variants converted into CAPS/dCAPS markers, 17 showed high level of polymorphism between low and high SPC genotypes. Assay of 16 of the polymorphic CAPS/dCAPS markers on an F population of the cross ICP 5529 (high SPC) × ICP 11605 (low SPC), resulted in four of the CAPS/dCAPS markers significantly (P < 0.05) co-segregated with SPC. In summary, four markers derived from mutations in four genes will be useful for enhancing/regulating SPC in pigeonpea crop improvement programs.

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“…Specifically, we envision the following lines of inquiry:

Establishing the cellular and small network-level functional endophenotype characteristic of SCZ using hiPSC-derived neurons. These experiments would take advantage of novel gene-editing methods, 56 which now allow replacement of large DNA segments, as well as the growing arsenal of optogenetic and chemogenetic manipulation tools 57–59 and optical reporters, 60 being developed under the BRAIN Initiative. 61 In this approach, we would rank patient-derived hiPSCs according to the number of high-risk variants, weighted by their strength of disease association, within a predefined set of genes, such as that comprising Table 1.

…”

Section: Comprehensive Model Of Scz Pathophysiologymentioning

confidence: 99%

Genetic evidence for role of integration of fast and slow neurotransmission in schizophrenia

et al. 2017

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The most recent genome-wide association studies (GWAS) of schizophrenia (SCZ) identified hundreds of risk variants potentially implicated in the disease. Further, novel statistical methodology designed for polygenic architecture revealed more potential risk variants. This can provide a link between individual genetic factors and the mechanistic underpinnings of SCZ. Intriguingly, a large number of genes coding for ionotropic and metabotropic receptors for various neurotransmitters—glutamate, γ-aminobutyric acid (GABA), dopamine, serotonin, acetylcholine and opioids—and numerous ion channels were associated with SCZ. Here, we review these findings from the standpoint of classical neurobiological knowledge of neuronal synaptic transmission and regulation of electrical excitability. We show that a substantial proportion of the identified genes are involved in intracellular cascades known to integrate ‘slow’ (G-protein-coupled receptors) and ‘fast’ (ionotropic receptors) neurotransmission converging on the protein DARPP-32. Inspection of the Human Brain Transcriptome Project database confirms that that these genes are indeed expressed in the brain, with the expression profile following specific developmental trajectories, underscoring their relevance to brain organization and function. These findings extend the existing pathophysiology hypothesis by suggesting a unifying role of dysregulation in neuronal excitability and synaptic integration in SCZ. This emergent model supports the concept of SCZ as an ‘associative’ disorder—a breakdown in the communication across different slow and fast neurotransmitter systems through intracellular signaling pathways—and may unify a number of currently competing hypotheses of SCZ pathophysiology.

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Genome-Editing Technologies: Principles and Applications

Cited by 297 publications

References 259 publications

Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality

Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality

Development of sequence-based markers for seed protein content in pigeonpea

Genetic evidence for role of integration of fast and slow neurotransmission in schizophrenia

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