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Cells
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CRISPR-Based Genome Editing in Translational Research—Second Edition
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CRISPR-Based Genome Editing in Translational Research—Second Edition

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell and Gene Therapy".

Deadline for manuscript submissions: closed (31 August 2024) | Viewed by 18534

Special Issue Editors

Dr. Jifeng Zhang

E-Mail Website
Guest Editor
Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Interests: genome; gene editing; cell biology; CRISPR/Cas9
Special Issues, Collections and Topics in MDPI journals
Dr. Dongshan Yang

E-Mail Website
Guest Editor
Center for Advanced Models and Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Interests: genome; gene editing; cell biology; CRISPR/Cas9
Special Issues, Collections and Topics in MDPI journals
Dr. Jie Xu

E-Mail Website
Guest Editor
Center for Advanced Models and Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Interests: genome; gene editing; cell biology; CRISPR/Cas9
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Emerging gene editing tools represented by CRISPR/Cas9 have had a significant impact on the translational biomedical research field. Thanks to their ease of use and high efficiency, they are widely used for the production of novel animal and cellular models and for the development of gene-editing-based therapy for genetic and nongenetic diseases. At the same time, many roadblocks remain in the path toward their eventual clinical applications, such as substantial off-target editing events which need to be minimized and a lack of efficient and safe in vivo delivery methods.

This Special Issue calls for research and review articles on any topics related to the translational application of CRISPR in modern biomedical research.

Dr. Jifeng Zhang
Dr. Dongshan Yang
Dr. Jie Xu
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

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Published Papers (7 papers)

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Research

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13 pages, 1869 KiB  
Article
Generation of Rhesus Macaque Embryos with Expanded CAG Trinucleotide Repeats in the Huntingtin Gene
by Junghyun Ryu, John P. Statz, William Chan, Kiana Oyama, Maggie Custer, Martin Wienisch, Richard Chen, Carol B. Hanna and Jon D. Hennebold
Cells 2024, 13(10), 829; https://doi.org/10.3390/cells13100829 - 13 May 2024
Viewed by 1250
Abstract
Huntington’s disease (HD) arises from expanded CAG repeats in exon 1 of the Huntingtin (HTT) gene. The resultant misfolded HTT protein accumulates within neuronal cells, negatively impacting their function and survival. Ultimately, HTT accumulation results in cell death, causing the development [...] Read more.
Huntington’s disease (HD) arises from expanded CAG repeats in exon 1 of the Huntingtin (HTT) gene. The resultant misfolded HTT protein accumulates within neuronal cells, negatively impacting their function and survival. Ultimately, HTT accumulation results in cell death, causing the development of HD. A nonhuman primate (NHP) HD model would provide important insight into disease development and the generation of novel therapies due to their genetic and physiological similarity to humans. For this purpose, we tested CRISPR/Cas9 and a single-stranded DNA (ssDNA) containing expanded CAG repeats in introducing an expanded CAG repeat into the HTT gene in rhesus macaque embryos. Analyses were conducted on arrested embryos and trophectoderm (TE) cells biopsied from blastocysts to assess the insertion of the ssDNA into the HTT gene. Genotyping results demonstrated that 15% of the embryos carried an expanded CAG repeat. The integration of an expanded CAG repeat region was successfully identified in five blastocysts, which were cryopreserved for NHP HD animal production. Some off-target events were observed in biopsies from the cryopreserved blastocysts. NHP embryos were successfully produced, which will help to establish an NHP HD model and, ultimately, may serve as a vital tool for better understanding HD’s pathology and developing novel treatments. Full article
(This article belongs to the Special Issue CRISPR-Based Genome Editing in Translational Research—Second Edition)
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14 pages, 1842 KiB  
Article
Simplifying Genotyping of Mutants from Genome Editing with a Parallel qPCR-Based iGenotype Index
by Liezhen Fu, Shouhong Wang, Lusha Liu, Yuki Shibata, Morihiro Okada, Nga Luu and Yun-Bo Shi
Cells 2024, 13(3), 247; https://doi.org/10.3390/cells13030247 - 29 Jan 2024
Viewed by 2658
Abstract
Targeted genome editing is a powerful tool in reverse genetic studies of gene function in many aspects of biological and pathological processes. The CRISPR/Cas system or engineered endonucleases such as ZFNs and TALENs are the most widely used genome editing tools that are [...] Read more.
Targeted genome editing is a powerful tool in reverse genetic studies of gene function in many aspects of biological and pathological processes. The CRISPR/Cas system or engineered endonucleases such as ZFNs and TALENs are the most widely used genome editing tools that are introduced into cells or fertilized eggs to generate double-strand DNA breaks within the targeted region, triggering cellular DNA repair through either homologous recombination or non-homologous end joining (NHEJ). DNA repair through the NHEJ mechanism is usually error-prone, leading to point mutations or indels (insertions and deletions) within the targeted region. Some of the mutations in embryos are germline transmissible, thus providing an effective way to generate model organisms with targeted gene mutations. However, point mutations and short indels are difficult to be effectively genotyped, often requiring time-consuming and costly DNA sequencing to obtain reliable results. Here, we developed a parallel qPCR assay in combination with an iGenotype index to allow simple and reliable genotyping. The genotype-associated iGenotype indexes converged to three simple genotype-specific constant values (1, 0, −1) regardless of allele-specific primers used in the parallel qPCR assays or gene mutations at wide ranges of PCR template concentrations, thus resulting in clear genotype-specific cutoffs, established through statistical analysis, for genotype identification. While we established such a genotyping assay in the Xenopus tropicalis model, the approach should be applicable to genotyping of any organism or cells and can be potentially used for large-scale, automated genotyping. Full article
(This article belongs to the Special Issue CRISPR-Based Genome Editing in Translational Research—Second Edition)
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15 pages, 4193 KiB  
Article
Generation and Characterization of a Zebrafish Model for ADGRV1-Associated Retinal Dysfunction Using CRISPR/Cas9 Genome Editing Technology
by Merel Stemerdink, Sanne Broekman, Theo Peters, Hannie Kremer, Erik de Vrieze and Erwin van Wijk
Cells 2023, 12(12), 1598; https://doi.org/10.3390/cells12121598 - 10 Jun 2023
Cited by 2 | Viewed by 2633
Abstract
Worldwide, around 40,000 people progressively lose their eyesight as a consequence of retinitis pigmentosa (RP) caused by pathogenic variants in the ADGRV1 gene, for which currently no treatment options exist. A model organism that mimics the human phenotype is essential to unravel the [...] Read more.
Worldwide, around 40,000 people progressively lose their eyesight as a consequence of retinitis pigmentosa (RP) caused by pathogenic variants in the ADGRV1 gene, for which currently no treatment options exist. A model organism that mimics the human phenotype is essential to unravel the exact pathophysiological mechanism underlying ADGRV1-associated RP, and to evaluate future therapeutic strategies. The introduction of CRISPR/Cas-based genome editing technologies significantly improved the possibilities of generating mutant models in a time- and cost-effective manner. Zebrafish have been recognized as a suitable model to study Usher syndrome-associated retinal dysfunction. Using CRISPR/Cas9 technology we introduced a 4bp deletion in adgrv1 exon 9 (adgrv1rmc22). Immunohistochemical analysis showed that Adgrv1 was absent from the region of the photoreceptor connecting cilium in the adgrv1rmc22 zebrafish retina. Here, the absence of Adgrv1 also resulted in reduced levels of the USH2 complex members usherin and Whrnb, suggesting that Adgrv1 interacts with usherin and Whrnb in zebrafish photoreceptors. When comparing adgrv1rmc22 zebrafish with wild-type controls, we furthermore observed increased levels of aberrantly localized rhodopsin in the photoreceptor cell body, and decreased electroretinogram (ERG) B-wave amplitudes which indicate that the absence of Adgrv1 results in impaired retinal function. Based on these findings we present the adgrv1rmc22 zebrafish as the first ADGRV1 mutant model that displays an early retinal dysfunction. Moreover, the observed phenotypic changes can be used as quantifiable outcome measures when evaluating the efficacy of future novel therapeutic strategies for ADGRV1-associated RP. Full article
(This article belongs to the Special Issue CRISPR-Based Genome Editing in Translational Research—Second Edition)
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Review

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34 pages, 2835 KiB  
Review
Navigating the CRISPR/Cas Landscape for Enhanced Diagnosis and Treatment of Wilson’s Disease
by Woong Choi, Seongkwang Cha and Kyoungmi Kim
Cells 2024, 13(14), 1214; https://doi.org/10.3390/cells13141214 - 18 Jul 2024
Cited by 1 | Viewed by 1822
Abstract
The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) system continues to evolve, thereby enabling more precise detection and repair of mutagenesis. The development of CRISPR/Cas-based diagnosis holds promise for high-throughput, cost-effective, and portable nucleic acid screening and genetic disease diagnosis. In [...] Read more.
The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) system continues to evolve, thereby enabling more precise detection and repair of mutagenesis. The development of CRISPR/Cas-based diagnosis holds promise for high-throughput, cost-effective, and portable nucleic acid screening and genetic disease diagnosis. In addition, advancements in transportation strategies such as adeno-associated virus (AAV), lentiviral vectors, nanoparticles, and virus-like vectors (VLPs) offer synergistic insights for gene therapeutics in vivo. Wilson’s disease (WD), a copper metabolism disorder, is primarily caused by mutations in the ATPase copper transporting beta (ATP7B) gene. The condition is associated with the accumulation of copper in the body, leading to irreversible damage to various organs, including the liver, nervous system, kidneys, and eyes. However, the heterogeneous nature and individualized presentation of physical and neurological symptoms in WD patients pose significant challenges to accurate diagnosis. Furthermore, patients must consume copper-chelating medication throughout their lifetime. Herein, we provide a detailed description of WD and review the application of novel CRISPR-based strategies for its diagnosis and treatment, along with the challenges that need to be overcome. Full article
(This article belongs to the Special Issue CRISPR-Based Genome Editing in Translational Research—Second Edition)
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14 pages, 1770 KiB  
Review
Prime Editing and DNA Repair System: Balancing Efficiency with Safety
by Karim Daliri, Jürgen Hescheler and Kurt Paul Pfannkuche
Cells 2024, 13(10), 858; https://doi.org/10.3390/cells13100858 - 17 May 2024
Viewed by 2102
Abstract
Prime editing (PE), a recent progression in CRISPR-based technologies, holds promise for precise genome editing without the risks associated with double-strand breaks. It can introduce a wide range of changes, including single-nucleotide variants, insertions, and small deletions. Despite these advancements, there is a [...] Read more.
Prime editing (PE), a recent progression in CRISPR-based technologies, holds promise for precise genome editing without the risks associated with double-strand breaks. It can introduce a wide range of changes, including single-nucleotide variants, insertions, and small deletions. Despite these advancements, there is a need for further optimization to overcome certain limitations to increase efficiency. One such approach to enhance PE efficiency involves the inhibition of the DNA mismatch repair (MMR) system, specifically MLH1. The rationale behind this approach lies in the MMR system’s role in correcting mismatched nucleotides during DNA replication. Inhibiting this repair pathway creates a window of opportunity for the PE machinery to incorporate the desired edits before permanent DNA repair actions. However, as the MMR system plays a crucial role in various cellular processes, it is important to consider the potential risks associated with manipulating this system. The new versions of PE with enhanced efficiency while blocking MLH1 are called PE4 and PE5. Here, we explore the potential risks associated with manipulating the MMR system. We pay special attention to the possible implications for human health, particularly the development of cancer. Full article
(This article belongs to the Special Issue CRISPR-Based Genome Editing in Translational Research—Second Edition)
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14 pages, 1200 KiB  
Review
CRISPR-Cas System Is an Effective Tool for Identifying Drug Combinations That Provide Synergistic Therapeutic Potential in Cancers
by Yuna Kim and Hyeong-Min Lee
Cells 2023, 12(22), 2593; https://doi.org/10.3390/cells12222593 - 9 Nov 2023
Viewed by 1623
Abstract
Despite numerous efforts, the therapeutic advancement for neuroblastoma and other cancer treatments is still ongoing due to multiple challenges, such as the increasing prevalence of cancers and therapy resistance development in tumors. To overcome such obstacles, drug combinations are one of the promising [...] Read more.
Despite numerous efforts, the therapeutic advancement for neuroblastoma and other cancer treatments is still ongoing due to multiple challenges, such as the increasing prevalence of cancers and therapy resistance development in tumors. To overcome such obstacles, drug combinations are one of the promising applications. However, identifying and implementing effective drug combinations are critical for achieving favorable treatment outcomes. Given the enormous possibilities of combinations, a rational approach is required to predict the impact of drug combinations. Thus, CRISPR-Cas-based and other approaches, such as high-throughput pharmacological and genetic screening approaches, have been used to identify possible drug combinations. In particular, the CRISPR-Cas system (Clustered Regularly Interspaced Short Palindromic Repeats) is a powerful tool that enables us to efficiently identify possible drug combinations that can improve treatment outcomes by reducing the total search space. In this review, we discuss the rational approaches to identifying, examining, and predicting drug combinations and their impact. Full article
(This article belongs to the Special Issue CRISPR-Based Genome Editing in Translational Research—Second Edition)
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25 pages, 2004 KiB  
Review
Clinical Approaches for Mitochondrial Diseases
by Seongho Hong, Sanghun Kim, Kyoungmi Kim and Hyunji Lee
Cells 2023, 12(20), 2494; https://doi.org/10.3390/cells12202494 - 20 Oct 2023
Cited by 5 | Viewed by 5638
Abstract
Mitochondria are subcontractors dedicated to energy production within cells. In human mitochondria, almost all mitochondrial proteins originate from the nucleus, except for 13 subunit proteins that make up the crucial system required to perform ‘oxidative phosphorylation (OX PHOS)’, which are expressed by the [...] Read more.
Mitochondria are subcontractors dedicated to energy production within cells. In human mitochondria, almost all mitochondrial proteins originate from the nucleus, except for 13 subunit proteins that make up the crucial system required to perform ‘oxidative phosphorylation (OX PHOS)’, which are expressed by the mitochondria’s self-contained DNA. Mitochondrial DNA (mtDNA) also encodes 2 rRNA and 22 tRNA species. Mitochondrial DNA replicates almost autonomously, independent of the nucleus, and its heredity follows a non-Mendelian pattern, exclusively passing from mother to children. Numerous studies have identified mtDNA mutation-related genetic diseases. The consequences of various types of mtDNA mutations, including insertions, deletions, and single base-pair mutations, are studied to reveal their relationship to mitochondrial diseases. Most mitochondrial diseases exhibit fatal symptoms, leading to ongoing therapeutic research with diverse approaches such as stimulating the defective OXPHOS system, mitochondrial replacement, and allotropic expression of defective enzymes. This review provides detailed information on two topics: (1) mitochondrial diseases caused by mtDNA mutations, and (2) the mechanisms of current treatments for mitochondrial diseases and clinical trials. Full article
(This article belongs to the Special Issue CRISPR-Based Genome Editing in Translational Research—Second Edition)
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