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Anil Dangi, Shuangjin Yu, Xunrong Luo
Newly emerging technologies are rapidly changing conventional approaches to organ transplantation. In the modern era, the key challenges to transplantation include (1) how to best individualize and possibly eliminate the need for life-long immunosuppression and (2) how to expand the donor pool suitable for human transplantation. This article aims to provide readers with an updated review of three new technologies that address these challenges. First, single-cell RNA sequencing technology is rapidly evolving and has recently been employed in settings related to transplantation...
February 13, 2019: Cellular & Molecular Immunology
Yajie Li, Erin C Mooney, Sara E Holden, Xia-Juan Xia, David J Cohen, Scott W Walsh, Averil Ma, Sinem E Sahingur
Deregulated immune response to a dysbiotic resident microflora within the oral cavity leads to chronic periodontal disease, local tissue destruction, and various systemic complications. To preserve tissue homeostasis, inflammatory signaling pathways involved in the progression of periodontitis must be tightly regulated. A20 (TNFAIP3), a ubiquitin-editing enzyme, has emerged as one of the key regulators of inflammation. Yet, the function of A20 in the oral mucosa and the biological pathways in which A20 mitigates periodontal inflammation remain elusive...
February 13, 2019: Journal of Immunology: Official Journal of the American Association of Immunologists
Elvira Román, Ioana Coman, Daniel Prieto, Rebeca Alonso-Monge, Jesús Pla
Clustered regularly interspaced short palindromic repeat (CRISPR) methodology is not only an efficient tool in gene editing but also an attractive platform to facilitate DNA, RNA, and protein interactions. We describe here the implementation of a CRISPR-based system to regulate expression in the clinically important yeast Candida albicans By fusing an allele of Streptococcus pyogenes Cas9 devoid of nuclease activity to a transcriptional repressor (Nrg1) or activator (Gal4), we were able to show specific repression or activation of the tester gene CAT1 , encoding the cytosolic catalase...
February 13, 2019: MSphere
Eric Deneault, Sean H White, Deivid C Rodrigues, P Joel Ross, Muhammad Faheem, Kirill Zaslavsky, Zhuozhi Wang, Roumiana Alexandrova, Giovanna Pellecchia, Wei Wei, Alina Piekna, Gaganjot Kaur, Jennifer L Howe, Vickie Kwan, Bhooma Thiruvahindrapuram, Susan Walker, Anath C Lionel, Peter Pasceri, Daniele Merico, Ryan K C Yuen, Karun K Singh, James Ellis, Stephen W Scherer
No abstract text is available yet for this article.
February 12, 2019: Stem Cell Reports
Baisong Lu, Parisa Javidi-Parsijani, Vishruti Makani, Farideh Mehraein-Ghomi, Walaa Mohamed Sarhan, Dongjun Sun, Kyung Whan Yoo, Zachary P Atala, Pin Lyu, Anthony Atala
The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) system discovered using bacteria has been repurposed for genome editing in human cells. Transient expression of the editor proteins (e.g. Cas9 protein) is desirable to reduce the risk of mutagenesis from off-target activity. Using the specific interaction between bacteriophage RNA-binding proteins and their RNA aptamers, we developed a system able to package up to 100 copies of Staphylococcus aureus Cas9 (SaCas9) mRNA in each lentivirus-like bionanoparticle (LVLP)...
February 13, 2019: Nucleic Acids Research
Nan He, Bradley H Rosen, Jaimie S Gray, Idil A Evans, Marina Zieger, Ziying Yan, Florie Borel, Bo Liang, Xingshen Sun, Shashanna R Moll, Michael H Brodsky, Christian Mueller, John F Engelhardt
RATIONALE: The most prevalent genetic cause of chronic obstructive pulmonary disease is alpha-1 antitrypsin (A1AT) deficiency, a disorder that has yet to be widely modeled in animals because of species-specific differences between rodents and humans. OBJECTIVES: To address these challenges, we engineered two A1AT ferret models using zygote gene editing to test the hypothesis that unopposed protease activity within the lung leads to emphysema and bronchitis. METHODS: Guide RNAs targeting exon 2 (for knockout) and exon 5 (for Z-allele mutation, Pi*Z) of the ferret A1AT gene were injected into ferret zygotes with Cas9 mRNA...
December 2018: Annals of the American Thoracic Society
Yasuhiro Kyono, Jacob O Kitzman, Stephen C J Parker
Variation in non-coding DNA, encompassing gene regulatory regions such as enhancers and promoters, contributes to risk for complex disorders, including type 2 diabetes. While genome-wide association studies have successfully identified hundreds of type 2 diabetes loci throughout the genome, the vast majority of these reside in non-coding DNA, which complicates the process of determining their functional significance and level of priority for further study. Here we review the methods used to experimentally annotate these non-coding variants, to nominate causal variants and to link them to diabetes pathophysiology...
February 12, 2019: Diabetologia
Kalina Paunovska, Alejandro J Da Silva Sanchez, Cory D Sago, Zubao Gan, Melissa P Lokugamage, Fatima Z Islam, Sujay Kalathoor, Brandon R Krupczak, James E Dahlman
Using mRNA to produce therapeutic proteins is a promising approach to treat genetic diseases. However, systemically delivering mRNA to cell types besides hepatocytes remains challenging. Fast identification of nanoparticle delivery (FIND) is a DNA barcode-based system designed to measure how over 100 lipid nanoparticles (LNPs) deliver mRNA that functions in the cytoplasm of target cells in a single mouse. By using FIND to quantify how 75 chemically distinct LNPs delivered mRNA to 28 cell types in vivo, it is found that an LNP formulated with oxidized cholesterol and no targeting ligand delivers Cre mRNA, which edits DNA in hepatic endothelial cells and Kupffer cells at 0...
February 12, 2019: Advanced Materials
Diane Seibert
This article explores the origin of the first cellular structures, briefly examines the process of evolution, explores some of the earlier challenges in human gene editing, explains how bacterial immune systems have provided the secret to a very powerful gene editing tool, and finally explores some of the very troubling ethical issues emerging with gene editing.
February 2019: Journal of the American Association of Nurse Practitioners
Jingyao Chen, Haitao Wang, Jianhui Bai, Wenjie Liu, Xiaojuan Liu, Dawei Yu, Tao Feng, Zhaolin Sun, Linlin Zhang, Linyuan Ma, Yiqing Hu, Yunlong Zou, Tan Tan, Jie Zhong, Man Hu, Xiaofei Bai, Dengke Pan, Yiming Xing, Yaofeng Zhao, Kegong Tian, Xiaoxiang Hu, Ning Li
Porcine reproductive and respiratory syndrome (PRRS) is a highly contagious disease and the most economically important disease of the swine industry worldwide. Highly pathogenic-PRRS virus (HP-PRRSV) is a variant of PRRSV, which caused high morbidity and mortality. Scavenger receptor CD163, which contains nine scavenger receptor cysteine-rich (SRCR) domains, is a key entry mediator for PRRSV. A previous study demonstrated that SRCR domain 5 (SRCR5), encoded by exon 7, was essential for PRRSV infection in vitro ...
2019: International Journal of Biological Sciences
Sandeep Soni, Donald B Kohn
Gene modification of hematopoietic stem cells is increasingly becoming popular as a therapeutic approach, given the recent approvals and the number of new applications for clinical trials targeting monogenetic and immunodeficiency disorders. Technological advances in stem cell selection, culture, transduction and gene editing now allow for efficient ex vivo genetic manipulation of stem cells. Gene-addition techniques using viral vectors (mainly retrovirus- and lentivirus-based) and gene editing using various targeted nuclease platforms (e...
February 8, 2019: Cytotherapy
Zhongwei Li, Toshikazu Araoka, Juan Carlos Izpisua Belmonte
During kidney development, Six2+ nephron progenitor cells (NPCs) generate nephrons, the functional units of the kidney. Isolating and expanding NPCs in vitro have enabled wide applications in both basic and translational research. Here we describe the methods to derive NPC lines from mouse embryonic kidneys in a 3D culture format as well as gene editing in the NPC lines.
2019: Methods in Molecular Biology
Benjamin P Kleinstiver, Alexander A Sousa, Russell T Walton, Y Esther Tak, Jonathan Y Hsu, Kendell Clement, Moira M Welch, Joy E Horng, Jose Malagon-Lopez, Irene Scarfò, Marcela V Maus, Luca Pinello, Martin J Aryee, J Keith Joung
Broad use of CRISPR-Cas12a (formerly Cpf1) nucleases1 has been hindered by the requirement for an extended TTTV protospacer adjacent motif (PAM)2 . To address this limitation, we engineered an enhanced Acidaminococcus sp. Cas12a variant (enAsCas12a) that has a substantially expanded targeting range, enabling targeting of many previously inaccessible PAMs. On average, enAsCas12a exhibits a twofold higher genome editing activity on sites with canonical TTTV PAMs compared to wild-type AsCas12a, and we successfully grafted a subset of mutations from enAsCas12a onto other previously described AsCas12a variants3 to enhance their activities...
February 11, 2019: Nature Biotechnology
Denis T Akan, Jennifer E Howes, Jiqing Sai, Allison L Arnold, Yugandhar Beesetty, Jason Phan, Edward T Olejniczak, Alex G Waterson, Stephen W Fesik
Activating mutations in RAS lead to oncogenesis by enhancing downstream signaling, such as through the MAPK and PI3K pathways. Therefore, therapeutically targeting RAS may perturb multiple signaling pathways simultaneously. One method for modulating RAS signaling is to target the activity of the guanine nucleotide exchange factor SOS1. Our laboratory has discovered compounds that bind to SOS1 and activate RAS. Interestingly, these SOS1 agonist compounds elicit biphasic modulation of ERK phosphorylation and simultaneous inhibition of AKT phosphorylation levels...
February 8, 2019: ACS Chemical Biology
Hanrui Zheng, Ting Liu, Tiantian Lei, Lea Girani, Yi Wang, Shaoping Deng
Organ transplantation is a crucial medical procedure, as it is often the only treatment for patients suffering from end-stage organ failure. Unfortunately, the shortage of donor organs limits the number of patients whose lives can be saved. Carrying out research on xenotransplantation with the aim of eventually replacing human organ transplants with those of animals is very promising, as it could effectively bridge the shortfall in donor organs. Thanks to the success of cloned pigs and to the emergence of gene-editing techniques, genetically modified pigs have come to be considered ideal animal donors for human xenotransplantation and have been widely used in basic research...
February 8, 2019: Xenotransplantation
Joon Eoh, Luo Gu
The emergence of the CRISPR-Cas9 gene editing system has brought much hope and excitement to the field of gene therapy and the larger scientific community. However, in order for CRISPR-based therapies to be translated to the clinical setting, there is an urgent need to develop optimized vectors for their delivery. The delivery vector is a crucial determinant of the therapeutic efficacy of gene editing and should be designed to accommodate various factors including the form of the payload, the physiological environment, and the potential immune responses...
February 8, 2019: Biomaterials Science
Peter P Nghiem, Joe N Kornegay
Therapies for Duchenne muscular dystrophy (DMD) must first be tested in animal models to determine proof-of-concept, efficacy, and importantly, safety. The murine and canine models for DMD are genetically homologous and most commonly used in pre-clinical testing. Although the mouse is a strong, proof-of-concept model, affected dogs show more analogous clinical and immunological disease progression compared to boys with DMD. As such, evaluating genetic therapies in the canine models may better predict response at the genetic, phenotypic, and immunological levels...
February 7, 2019: Human Genetics
Dalia Fleifel, Mai Atef Rahmoon, Abdelrahman AlOkda, Mostafa Nasr, Menattallah Elserafy, Sherif F El-Khamisy
Stem cells serve as potential therapeutics due to their high proliferative capacity, low immunogenic reactivity and their differentiating capabilities. Several pre-clinical and early-stage clinical studies are carried out to treat genetic diseases, cancers and neurodegenerative disorders with promising preliminary results. However, there are still many challenges that scientists are trying to overcome such as the unclear expression profile of stem cells in vivo, the homing of stem cells to the site of injury and their potential immune-reactivity...
December 2018: Journal, Genetic Engineering & Biotechnology
Yuki Yoshino, Shino Endo, Zhenghao Chen, Huicheng Qi, Gou Watanabe, Natsuko Chiba
Homologous recombination (HR) contributes to the repair of DNA double-strand breaks (DSBs) and inter-strand crosslinks. The HR activity in cancer cells can be used to predict their sensitivity to DNA-damaging agents that cause these damages. To evaluate HR activity, we developed a system called Assay for Site-specific HR Activity (ASHRA), in which cells are transiently transfected with an expression vector for CRISPR/Cas9 and a HR donor sequence containing a marker gene. DSBs are created by Cas9 and then repaired by HR using donor vector sequences homologous to the target gene...
February 7, 2019: Scientific Reports
Felice Ho-Ching Tsang, Cheuk-Ting Law, Chloe Tsz-Ching Tang, Carol Lai-Hung Cheng, Don Wai-Ching Chin, Vincy Wing-Sum Tam, Lai Wei, Carmen Chak-Lui Wong, Irene Oi-Lin Ng, Chun-Ming Wong
Hepatocellular carcinoma (HCC) cells exploit an aberrant transcriptional program to sustain their infinite growth and progression. Emerging evidence indicates that the continuous and robust transcription of oncogenes in cancer cells is often driven by super-enhancers (SEs). In this study, we systematically compared the SE-landscapes between normal liver and HCC cells and revealed that the cis-acting SE-landscape was extensively reprogrammed during liver carcinogenesis. HCC cells acquired SEs at multiple prominent oncogenes to drive their vigorous expression...
February 5, 2019: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
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