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Bingjie Shi, Juan Li, Xuanling Shi, Wenxu Jia, Yi Wen, Xiongbing Hu, Fengfeng Zhuang, Jianzhong Xi, Linqi Zhang
Transcription activator-like effector nuclease (TALEN) represents a valuable tool for genomic engineering due to its single-nucleotide precision, high nuclease activity and low cytotoxicity. We report here systematic design and characterization of twenty eight novel TALENs targeting multiple regions of CCR5 gene (CCR5-TALEN) which encodes the co-receptor critical for entry of human immunodeficiency virus type I (HIV-1). By systemic characterization of these CCR5-TALENs, we have identified one (CCR5-TALEN-515) with higher nuclease activity, specificity and lower cytotoxicity compared to zinc-finger nuclease (CCR5-ZFN) currently undergoing clinical trials...
October 3, 2016: Journal of Acquired Immune Deficiency Syndromes: JAIDS
Sandeep Kumar, Andrew Worden, Stephen Novak, Ryan Lee, Joseph F Petolino
A gene targeting method has been developed, which allows the conversion of 'breeding stacks', containing unlinked transgenes into a 'molecular stack' and thereby circumventing the breeding challenges associated with transgene segregation. A gene targeting method has been developed for converting two unlinked trait loci into a single locus transgene stack. The method utilizes intra-genomic homologous recombination (IGHR) between stably integrated target and donor loci which share sequence homology and nuclease cleavage sites whereby the donor contains a promoterless herbicide resistance transgene...
November 2016: Planta
Kyung-Rok Yu, Hannah Natanson, Cynthia E Dunbar
Hematopoietic stem and progenitor cells (HSPCs) have great therapeutic potential because of their ability to both self-renew and differentiate. It has been proposed that, given their unique properties, a small number of genetically modified HSPCs could accomplish lifelong, corrective reconstitution of the entire hematopoietic system in patients with various hematologic disorders. Scientists have demonstrated that gene addition therapies-targeted to HSPCs and using integrating retroviral vectors-possess clear clinical benefits in multiple diseases, among them immunodeficiencies, storage disorders, and hemoglobinopathies...
August 2, 2016: Human Gene Therapy
Zoe Hilioti, Ioannis Ganopoulos, Sabna Ajith, Ioannis Bossis, Athanasios Tsaftaris
A selection-free, highly efficient targeted mutagenesis approach based on a novel ZFN monomer arrangement for genome engineering in tomato reveals plant trait modifications. How to achieve precise gene targeting in plants and especially in crops remains a long-sought goal for elucidating gene function and advancing molecular breeding. To address this issue, zinc finger nuclease (ZFN)-based technology was developed for the Solanum lycopersicum seed system. A ZFN architecture design with an intronic sequence between the two DNA recognition sites was evaluated for its efficiency in targeted gene mutagenesis...
November 2016: Plant Cell Reports
Konrad Fischer, Simone Kraner-Scheiber, Björn Petersen, Beate Rieblinger, Anna Buermann, Tatiana Flisikowska, Krzysztof Flisikowski, Susanne Christan, Marlene Edlinger, Wiebke Baars, Mayuko Kurome, Valeri Zakhartchenko, Barbara Kessler, Elena Plotzki, Izabela Szczerbal, Marek Switonski, Joachim Denner, Eckhard Wolf, Reinhard Schwinzer, Heiner Niemann, Alexander Kind, Angelika Schnieke
Xenotransplantation from pigs could alleviate the shortage of human tissues and organs for transplantation. Means have been identified to overcome hyperacute rejection and acute vascular rejection mechanisms mounted by the recipient. The challenge is to combine multiple genetic modifications to enable normal animal breeding and meet the demand for transplants. We used two methods to colocate xenoprotective transgenes at one locus, sequential targeted transgene placement - 'gene stacking', and cointegration of multiple engineered large vectors - 'combineering', to generate pigs carrying modifications considered necessary to inhibit short to mid-term xenograft rejection...
2016: Scientific Reports
S Antony Ceasar, Vinothkumar Rajan, Sergey V Prykhozhij, Jason N Berman, S Ignacimuthu
The clustered, regularly interspaced, short palindromic repeat (CRISPR) and CRISPR associated protein 9 (Cas9) system discovered as an adaptive immunity mechanism in prokaryotes has emerged as the most popular tool for the precise alterations of the genomes of diverse species. CRISPR/Cas9 system has taken the world of genome editing by storm in recent years. Its popularity as a tool for altering genomes is due to the ability of Cas9 protein to cause double-stranded breaks in DNA after binding with short guide RNA molecules, which can be produced with dramatically less effort and expense than required for production of transcription-activator like effector nucleases (TALEN) and zinc-finger nucleases (ZFN)...
September 2016: Biochimica et Biophysica Acta
Kelsey C Patterson, Virginia E Hawkins, Kara M Arps, Daniel K Mulkey, Michelle L Olsen
Since the identification of MECP2 as the causative gene in the majority of Rett Syndrome (RTT) cases, transgenic mouse models have played a critical role in our understanding of this disease. The use of additional mammalian RTT models offers the promise of further elucidating critical early mechanisms of disease as well as providing new avenues for translational studies. We have identified significant abnormalities in growth as well as motor and behavioral function in a novel zinc-finger nuclease model of RTT utilizing both male and female rats throughout development...
June 21, 2016: Human Molecular Genetics
Yujia Cai, Anders Laustsen, Yan Zhou, Chenglong Sun, Mads Valdemar Anderson, Shengting Li, Niels Uldbjerg, Yonglun Luo, Martin R Jakobsen, Jacob Giehm Mikkelsen
Biased integration remains a key challenge for gene therapy based on lentiviral vector technologies. Engineering of next-generation lentiviral vectors targeting safe genomic harbors for insertion is therefore of high relevance. In a previous paper (Cai et al., 2014a), we showed the use of integrase-defective lentiviral vectors (IDLVs) as carriers of complete gene repair kits consisting of zinc-finger nuclease (ZFN) proteins and repair sequences, allowing gene correction by homologous recombination (HR). Here, we follow this strategy to engineer ZFN-loaded IDLVs that insert transgenes by a homology-driven mechanism into safe loci...
2016: ELife
Daniel Stone, Nixon Niyonzima, Keith R Jerome
Engineered endonucleases such as homing endonucleases (HEs), zinc finger nucleases (ZFNs), Tal-effector nucleases (TALENS) and the RNA-guided engineered nucleases (RGENs or CRISPR/Cas9) can target specific DNA sequences for cleavage, and are proving to be valuable tools for gene editing. Recently engineered endonucleases have shown great promise as therapeutics for the treatment of genetic disease and infectious pathogens. In this review, we discuss recent efforts to use the HE, ZFN, TALEN and CRISPR/Cas9 gene-editing platforms as antiviral therapeutics...
September 2016: Human Genetics
Faheem Ahmed Khan, Nuruliarizki Shinta Pandupuspitasari, Huang Chun-Jie, Zhou Ao, Muhammad Jamal, Ali Zohaib, Farhan Ahmed Khan, Muthia Raihana Hakim, Zhang ShuJun
Cancer is caused by a series of alterations in genome and epigenome mostly resulting in activation of oncogenes or inactivation of cancer suppressor genes. Genetic engineering has become pivotal in the treatment of cancer and other genetic diseases, especially the formerly-niche use of clustered regularly interspaced short palindromic repeats (CRISPR) associated with Cas9. In defining its superior use, we have followed the recent advances that have been made in producing CRISPR/Cas9 as a therapy of choice. We also provide important genetic mutations where CRISPRs can be repurposed to create adaptive immunity to fight carcinomas and edit genetic mutations causing it...
May 26, 2016: Oncotarget
Z Bősze, P Major, I Baczkó, K E Odening, L Bodrogi, L Hiripi, A Varró
Since the creation of the first transgenic rabbit thirty years ago, pronuclear microinjection remained the single applied method and resulted in numerous important rabbit models of human diseases, including cardiac deficiencies, albeit with low efficiency. For additive transgenesis a novel transposon mediated method, e.g., the Sleeping Beauty transgenesis, increased the efficiency, and its application to create cardiac disease models is expected in the near future. The targeted genome engineering nuclease family, e...
July 2016: Progress in Biophysics and Molecular Biology
Xuemei Zhang, Liqin Wang, Yangsheng Wu, Wenrong Li, Jing An, Fuchun Zhang, Mingjun Liu
Myostatin (MSTN) can negatively regulate the growth and development of skeletal muscle, and natural mutations can cause "double-muscling" trait in animals. In order to block the inhibiting effect of MSTN on muscle growth, we transferred zinc-finger nucleases (ZFN) which targeted sheep MSTN gene into cultured fibroblasts. Gene targeted colonies were isolated from transfected fibroblasts by serial dilution culture and screened by sequencing. Two colonies were identified with mono-allele mutation and one colony with bi-allelic deletion...
October 2016: Asian-Australasian Journal of Animal Sciences
Mansoureh Shahbazi Dastjerdeh, Shirin Kouhpayeh, Faezeh Sabzehei, Hossein Khanahmad, Mansour Salehi, Zahra Mohammadi, Laleh Shariati, Zahra Hejazi, Parisa Rabiei, Mostafa Manian
BACKGROUND: The evolution of antibiotic-resistant bacteria (ARB) and antibiotic-resistance genes (ARGs) has been accelerated recently by the indiscriminate application of antibiotics. Antibiotic resistance has challenged the success of medical interventions and therefore is considered a hazardous threat to human health. OBJECTIVES: The present study aimed to describe the use of zinc finger nuclease (ZFN) technology to target and disrupt a plasmid-encoded β-lactamase, which prevents horizontal gene transfer-mediated evolution of ARBs...
January 2016: Jundishapur Journal of Microbiology
Manjunath N Swamy, Haoquan Wu, Premlata Shankar
RNA interference (RNAi) provides a powerful tool to silence specific gene expression and has been widely used to suppress host factors such as CCR5 and/or viral genes involved in HIV-1 replication. Newer nuclease-based gene-editing technologies, such as zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN) and the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system, also provide powerful tools to ablate specific genes. Because of differences in co-receptor usage and the high mutability of the HIV-1 genome, a combination of host factors and viral genes needs to be suppressed for effective prevention and treatment of HIV-1 infection...
August 1, 2016: Advanced Drug Delivery Reviews
Zhou Xiangchun, Xing Yongzhong
Plant genome can be modified via current biotechnology with high specificity and excellent efficiency. Zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN) and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system are the key engineered nucleases used in the genome editing. Genome editing techniques enable gene targeted mutagenesis, gene knock-out, gene insertion or replacement at the target sites during the endogenous DNA repair process, including non-homologous end joining (NHEJ) and homologous recombination (HR), triggered by the induction of DNA double-strand break (DSB)...
March 2016: Yi Chuan, Hereditas
Ganesan Govindan, Sivaprakash Ramalingam
Recent advances in the targeted genome engineering enable molecular biologists to generate sequence specific modifications with greater efficiency and higher specificity in complex eukaryotic genomes. Programmable site-specific DNA cleavage reagents and cellular DNA repair mechanisms have made this possible. These reagents have become powerful tools for delivering a site-specific genomic double-strand break (DSB) at the desired chromosomal locus, which produces sequence alterations through error-prone non-homologous end joining (NHEJ) resulting in gene inactivations/knockouts...
November 2016: Journal of Cellular Physiology
Cong Li, Wenguang Cao
Clustered regulatory interspaced short palindromic repeats (CRISPR) found in bacteria and archaea genome that contains multiple short repeats loci, provides acquired immunity against invading foreign DNA via RNA-guided DNA cleavage. The first inkling of this hot new genetic engineering tool turned up in 1987, when a research team observed an oddly repetitive sequence at one end of a bacterial gene. Now three types of CRISPR/Cas system have been identified: types I, II and III. In the type II CRISPR/Cas9 system, short segments of foreign DNA termed 'spacers' are integrated within the CRISPR genomic loci, transcribed and processed into short CRISPR RNA (crRNA)...
November 2015: Sheng Wu Gong Cheng Xue Bao, Chinese Journal of Biotechnology
Rajagopal N Aravalli, Clifford J Steer
INTRODUCTION: More than 100 liver-related disorders are caused by mutations in a single gene. These include both inherited and acquired genetic disorders. The development of nucleic acid-based therapies for liver diseases has been severely restricted due to many undesirable side effects and methodological limitations. AREAS COVERED: In recent years, however, efforts have been intensified to address these issues, and to develop liver-targeted approaches using novel gene editing technologies, including ZFN, TALEN, CRISPR/Cas and PITCh...
2016: Expert Opinion on Biological Therapy
Dustin J Landau, Elizabeth Drake Brooks, Pablo Perez-Pinera, Hiruni Amarasekara, Adam Mefferd, Songtao Li, Andrew Bird, Charles A Gersbach, Dwight D Koeberl
Glycogen storage disease type Ia (GSD Ia) is caused by glucose-6-phosphatase (G6Pase) deficiency in association with severe, life-threatening hypoglycemia that necessitates lifelong dietary therapy. Here we show that use of a zinc-finger nuclease (ZFN) targeted to the ROSA26 safe harbor locus and a ROSA26-targeting vector containing a G6PC donor transgene, both delivered with adeno-associated virus (AAV) vectors, markedly improved survival of G6Pase knockout (G6Pase-KO) mice compared with mice receiving the donor vector alone (P < 0...
April 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
Zhenkui Qin, Yun Li, Baofeng Su, Qi Cheng, Zhi Ye, Dayan A Perera, Michael Fobes, Mei Shang, Rex A Dunham
Channel catfish (Ictalurus punctatus) is the most important freshwater aquaculture species in the USA. Genetically enhanced fish that are sterile could both profit the catfish industry and reduce potential environmental and ecological risks. As the first step to generate sterile channel catfish, three sets of zinc finger nuclease (ZFN) plasmids targeting the luteinizing hormone (LH) gene were designed and electroporated into one-cell embryos, different concentrations were introduced, and the Cel-I assay was conducted to detect mutations...
April 2016: Marine Biotechnology
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