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Genome Editing human

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https://www.readbyqxmd.com/read/29243558/ex-vivo-and-in-vivo-genome-editing-a-regulatory-scientific-framework-from-early-development-to-clinical-implementation
#1
Houria Bachtarzi
Recent advances in human genome science have paved the way to a new class of human gene therapies based on gene editing, with the potential to provide a long-lasting curative strategy for many debilitating and complex disorders, for which there is an unmet medical need. Therapeutic genome editing encompasses both ex vivo and in vivo gene correction modalities, for which similar and also application-specific considerations apply, which dictate the overall strategy to be followed from a scientific, clinical and regulatory perspective...
December 15, 2017: Regenerative Medicine
https://www.readbyqxmd.com/read/29237052/multimode-drug-inducible-crispr-cas9-devices-for-transcriptional-activation-and-genome-editing
#2
Jia Lu, Chen Zhao, Yingze Zhao, Jingfang Zhang, Yue Zhang, Li Chen, Qiyuan Han, Yue Ying, Shuai Peng, Runna Ai, Yu Wang
Precise investigation and manipulation of dynamic biological processes often requires molecular modulation in a controlled inducible manner. The clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) has emerged as a versatile tool for targeted gene editing and transcriptional programming. Here, we designed and vigorously optimized a series of Hybrid drug Inducible CRISPR/Cas9 Technologies (HIT) for transcriptional activation by grafting a mutated human estrogen receptor (ERT2) to multiple CRISPR/Cas9 systems, which renders them 4-hydroxytamoxifen (4-OHT) inducible for the access of genome...
December 9, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29236091/noncoding-copy-number-variations-are-associated-with-congenital-limb-malformation
#3
Ricarda Flöttmann, Bjørt K Kragesteen, Sinje Geuer, Magdalena Socha, Lila Allou, Anna Sowińska-Seidler, Laure Bosquillon de Jarcy, Johannes Wagner, Aleksander Jamsheer, Barbara Oehl-Jaschkowitz, Lars Wittler, Deepthi de Silva, Ingo Kurth, Idit Maya, Fernando Santos-Simarro, Wiebke Hülsemann, Eva Klopocki, Roger Mountford, Alan Fryer, Guntram Borck, Denise Horn, Pablo Lapunzina, Meredith Wilson, Bénédicte Mascrez, Denis Duboule, Stefan Mundlos, Malte Spielmann
PurposeCopy-number variants (CNVs) are generally interpreted by linking the effects of gene dosage with phenotypes. The clinical interpretation of noncoding CNVs remains challenging. We investigated the percentage of disease-associated CNVs in patients with congenital limb malformations that affect noncoding cis-regulatory sequences versus genes sensitive to gene dosage effects.MethodsWe applied high-resolution copy-number analysis to 340 unrelated individuals with isolated limb malformation. To investigate novel candidate CNVs, we re-engineered human CNVs in mice using clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing...
October 12, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/29230380/the-axolotl-limb-regeneration-model-as-a-discovery-tool-for-engineering-the-stem-cell-niche
#4
Negar Seyedhassantehrani, Takayoshi Otsuka, Shambhavi Singh, David M Gardiner
Purpose of review: Recent advances in genomics and gene editing have expanded the range of model organisms to include those with interesting biological capabilities such as regeneration. Among these are the classic models of regeneration biology, the salamander. Although stimulating endogenous regeneration in humans likely is many years away, with advances in stem cell biology and biomedical engineering (e.g. bio-inspired materials), it is evident that there is great potential to enhance regenerative outcomes by approaching the problem from an engineering perspective...
September 2017: Current Stem Cell Reports
https://www.readbyqxmd.com/read/29229813/human-genetic-variation-alters-crispr-cas9-on-and-off-targeting-specificity-at-therapeutically-implicated-loci
#5
Samuel Lessard, Laurent Francioli, Jessica Alfoldi, Jean-Claude Tardif, Patrick T Ellinor, Daniel G MacArthur, Guillaume Lettre, Stuart H Orkin, Matthew C Canver
The CRISPR-Cas9 nuclease system holds enormous potential for therapeutic genome editing of a wide spectrum of diseases. Large efforts have been made to further understanding of on- and off-target activity to assist the design of CRISPR-based therapies with optimized efficacy and safety. However, current efforts have largely focused on the reference genome or the genome of cell lines to evaluate guide RNA (gRNA) efficiency, safety, and toxicity. Here, we examine the effect of human genetic variation on both on- and off-target specificity...
December 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29228717/somatic-prdm2-c-4467dela-mutations-in-colorectal-cancers-control-histone-methylation-and-tumor-growth
#6
Tatjana Pandzic, Veronica Rendo, Jinyeong Lim, Chatarina Larsson, Jimmy Larsson, Ivaylo Stoimenov, Snehangshu Kundu, Muhammad Akhtar Ali, Mats Hellström, Liqun He, Anders M Lindroth, Tobias Sjöblom
The chromatin modifier PRDM2/RIZ1 is inactivated by mutation in several forms of cancer and is a putative tumor suppressor gene. Frameshift mutations in the C-terminal region of PRDM2, affecting (A)8 or (A)9 repeats within exon 8, are found in one third of colorectal cancers with microsatellite instability, but the contribution of these mutations to colorectal tumorigenesis is unknown. To model somatic mutations in microsatellite unstable tumors, we devised a general approach to perform genome editing while stabilizing the mutated nucleotide repeat...
November 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29224783/in%C3%A2-vivo-target-gene-activation-via-crispr-cas9-mediated-trans-epigenetic-modulation
#7
Hsin-Kai Liao, Fumiyuki Hatanaka, Toshikazu Araoka, Pradeep Reddy, Min-Zu Wu, Yinghui Sui, Takayoshi Yamauchi, Masahiro Sakurai, David D O'Keefe, Estrella Núñez-Delicado, Pedro Guillen, Josep M Campistol, Cheng-Jang Wu, Li-Fan Lu, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte
Current genome-editing systems generally rely on inducing DNA double-strand breaks (DSBs). This may limit their utility in clinical therapies, as unwanted mutations caused by DSBs can have deleterious effects. CRISPR/Cas9 system has recently been repurposed to enable target gene activation, allowing regulation of endogenous gene expression without creating DSBs. However, in vivo implementation of this gain-of-function system has proven difficult. Here, we report a robust system for in vivo activation of endogenous target genes through trans-epigenetic remodeling...
November 30, 2017: Cell
https://www.readbyqxmd.com/read/29219081/whole-genome-analysis-of-crispr-cas9-sgrna-off-target-homologies-via-an-efficient-computational-algorithm
#8
Hong Zhou, Michael Zhou, Daisy Li, Joseph Manthey, Ekaterina Lioutikova, Hong Wang, Xiao Zeng
BACKGROUND: The beauty and power of the genome editing mechanism, CRISPR Cas9 endonuclease system, lies in the fact that it is RNA-programmable such that Cas9 can be guided to any genomic loci complementary to a 20-nt RNA, single guide RNA (sgRNA), to cleave double stranded DNA, allowing the introduction of wanted mutations. Unfortunately, it has been reported repeatedly that the sgRNA can also guide Cas9 to off-target sites where the DNA sequence is homologous to sgRNA. RESULTS: Using human genome and Streptococcus pyogenes Cas9 (SpCas9) as an example, this article mathematically analyzed the probabilities of off-target homologies of sgRNAs and discovered that for large genome size such as human genome, potential off-target homologies are inevitable for sgRNA selection...
November 17, 2017: BMC Genomics
https://www.readbyqxmd.com/read/29218308/opportunities-for-crispr-cas9-gene-editing-in-retinal-regeneration-research
#9
REVIEW
Leah J Campbell, David R Hyde
While retinal degeneration and disease results in permanent damage and vision loss in humans, the severely damaged zebrafish retina has a high capacity to regenerate lost neurons and restore visual behaviors. Advancements in understanding the molecular and cellular basis of this regeneration response give hope that strategies and therapeutics may be developed to restore sight to blind and visually-impaired individuals. Our current understanding has been facilitated by the amenability of zebrafish to molecular tools, imaging techniques, and forward and reverse genetic approaches...
2017: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/29215041/crispr-cas9-delivery-with-one-single-adenoviral-vector-devoid-of-all-viral-genes
#10
Eric Ehrke-Schulz, Maren Schiwon, Theo Leitner, Stephan Dávid, Thorsten Bergmann, Jing Liu, Anja Ehrhardt
The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system revolutionized the field of gene editing but viral delivery of the CRISPR/Cas9 system has not been fully explored. Here we adapted clinically relevant high-capacity adenoviral vectors (HCAdV) devoid of all viral genes for the delivery of the CRISPR/Cas9 machinery using a single viral vector. We present a platform enabling fast transfer of the Cas9 gene and gRNA expression units into the HCAdV genome including the option to choose between constitutive or inducible Cas9 expression and gRNA multiplexing...
December 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29211501/viral-subversion-of-apobec3s-lessons-for-anti-tumor-immunity-and-tumor-immunotherapy
#11
Faezeh Borzooee, Mahdi Asgharpour, Emma Quinlan, Michael D Grant, Mani Larijani
APOBEC3s (A3) are endogenous DNA-editing enzymes that are expressed in immune cells including T lymphocytes. A3s target and mutate the genomes of retroviruses that infect immune tissues such as the human immunodeficiency virus (HIV). Therefore, A3s were classically defined as host anti-viral innate immune factors. In contrast, we and others showed that A3s can also benefit the virus by mediating escape from adaptive immune recognition and drugs. Crucially, whether A3-mediated mutations help or hinder HIV, is not up to chance...
December 6, 2017: International Reviews of Immunology
https://www.readbyqxmd.com/read/29210109/xenotransplantation-back-to-the-future
#12
REVIEW
Raphael P H Meier, Yannick D Muller, Alexandre Balaphas, Philippe Morel, Manuel Pascual, Jörg D Seebach, Leo H Buhler
The field of xenotransplantation has fluctuated between great optimism and doubts over the last 50 years. The initial clinical attempts were extremely ambitious but faced technical and ethical issues that prompted the research community to go back to preclinical studies. Important players left the field due to perceived xenozoonotic risks and the lack of progress in pig-to-non-human-primate transplant models. Initial apparently unsurmountable issues appear now to be possible to overcome due to progress of genetic engineering, allowing the generation of multiple-xenoantigen knockout pigs that express human transgenes and the genome-wide inactivation of porcine endogenous retroviruses...
December 5, 2017: Transplant International: Official Journal of the European Society for Organ Transplantation
https://www.readbyqxmd.com/read/29209906/the-fourth-annual-brds-on-genome-editing-and-silencing-for-precision-medicines
#13
Amit Kumar Chaudhary, Rajan Sharma Bhattarai, Ram I Mahato
Precision medicine is promising for treating human diseases, as it focuses on tailoring drugs to a patient's genes, environment, and lifestyle. The need for personalized medicines has opened the doors for turning nucleic acids into therapeutics. Although gene therapy has the potential to treat and cure genetic and acquired diseases, it needs to overcome certain obstacles before creating the overall prescription drugs. Recent advancement in the life science has helped to understand the effective manipulation and delivery of genome-engineering tools better...
December 5, 2017: Drug Delivery and Translational Research
https://www.readbyqxmd.com/read/29208606/emerging-role-of-crispr-cas9-technology-for-micrornas-editing-in-cancer-research
#14
REVIEW
Guillermo Aquino-Jarquin
MicroRNAs (miRNA) are small, noncoding RNA molecules with a master role in the regulation of important tasks in different critical processes of cancer pathogenesis. Because there are different miRNAs implicated in all the stages of cancer, for example, functioning as oncogenes, this makes these small molecules suitable targets for cancer diagnosis and therapy. RNA-mediated interference has been one major approach for sequence-specific regulation of gene expression in eukaryotic organisms. Recently, the CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 system, first identified in bacteria and archaea as an adaptive immune response to invading genetic material, has been explored as a sequence-specific molecular tool for editing genomic sequences for basic research in life sciences and for therapeutic purposes...
December 5, 2017: Cancer Research
https://www.readbyqxmd.com/read/29205102/crispr-cas9-editing-of-the-mouse-thra-gene-produces-models-with-variable-resistance-to-thyroid-hormone
#15
Suzy Markossian, Romain Guyot, Sabine Richard, Marie Teixeira, Nadine Aguilera, Mathilde Bouchet, Michelina Plateroti, Wenyue Guan, Karine Gauthier, Denise Aubert, Frederic Flamant
Resistance to thyroid hormone due to THRA mutations (RTHα) is a recently discovered genetic disease, displaying important variability in its clinical presentation. The mutations alter the function of TRα1, one of the two nuclear receptors for thyroid hormone. Our aim was to understand the relationship between specific THRA mutations and phenotype. We used CRISPR/Cas9 genome editing to generate 5 new mouse models of RTHα, with frameshift or missense mutations. Like human patients, mutant mice displayed a hypothyroid-like phenotype, with altered development...
December 5, 2017: Thyroid: Official Journal of the American Thyroid Association
https://www.readbyqxmd.com/read/29204648/aav-crispr-cas9-mediated-depletion-of-vegfr2-blocks-angiogenesis-in-vitro
#16
Wenyi Wu, Yajian Duan, Gaoen Ma, Guohong Zhou, Cindy Windhol, Patricia A D'Amore, Hetian Lei
Purpose: Pathologic angiogenesis is a component of many diseases, including neovascular age-related macular degeneration, proliferation diabetic retinopathy, as well as tumor growth and metastasis. The purpose of this project was to examine whether the system of adeno-associated viral (AAV)-mediated CRISPR (clustered regularly interspaced short palindromic repeats)-associated endonuclease (Cas)9 can be used to deplete expression of VEGF receptor 2 (VEGFR2) in human vascular endothelial cells in vitro and thus suppress its downstream signaling events...
December 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29203900/intracellular-immunization-against-hiv-infection-with-an-intracellular-antibody-that-mimics-hiv-integrase-binding-to-the-cellular-ledgf-protein
#17
Leyuan Bao, Clare Hannon, Abimael Cruz-Mignoni, Denis Ptchelkine, Mei-Yi Sun, Ami Miller, Wilawan Bunjobpol, Camilo E Quevedo, Mariliza Derveni, Jennifer Chambers, Alison Simmons, Simon E V Phillips, Terence H Rabbitts
Preventing the protein-protein interaction of the cellular chromatin binding protein Lens Epithelium-Derived Growth Factor (LEDGF) and human immunodeficiency virus (HIV) integrase is an important possible strategy for anti-viral treatment for AIDS. We have used Intracellular Antibody Capture technology to isolate a single VH antibody domain that binds to LEDGF. The crystal structure of the LEDGF-VH complex reveals that the single domain antibody mimics the effect of binding of HIV integrase to LEDGF which is crucial for HIV propagation...
December 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29203824/genetic-engineering-in-nonhuman-primates-for-human-disease-modeling
#18
REVIEW
Kenya Sato, Erika Sasaki
Nonhuman primate (NHP) experimental models have contributed greatly to human health research by assessing the safety and efficacy of newly developed drugs, due to their physiological and anatomical similarities to humans. To generate NHP disease models, drug-inducible methods, and surgical treatment methods have been employed. Recent developments in genetic and developmental engineering in NHPs offer new options for producing genetically modified disease models. Moreover, in recent years, genome-editing technology has emerged to further promote this trend and the generation of disease model NHPs has entered a new era...
December 4, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/29199274/recent-developments-in-genetics-and-medically-assisted-reproduction-from-research-to-clinical-applications
#19
REVIEW
J C Harper, K Aittomäki, P Borry, M C Cornel, G de Wert, W Dondorp, J Geraedts, L Gianaroli, K Ketterson, I Liebaers, K Lundin, H Mertes, M Morris, G Pennings, K Sermon, C Spits, S Soini, A P A van Montfoort, A Veiga, J R Vermeesch, S Viville, M Macek
Two leading European professional societies, the European Society of Human Genetics and the European Society for Human Reproduction and Embryology, have worked together since 2004 to evaluate the impact of fast research advances at the interface of assisted reproduction and genetics, including their application into clinical practice. In September 2016, the expert panel met for the third time. The topics discussed highlighted important issues covering the impacts of expanded carrier screening, direct-to-consumer genetic testing, voiding of the presumed anonymity of gamete donors by advanced genetic testing, advances in the research of genetic causes underlying male and female infertility, utilisation of massively parallel sequencing in preimplantation genetic testing and non-invasive prenatal screening, mitochondrial replacement in human oocytes, and additionally, issues related to cross-generational epigenetic inheritance following IVF and germline genome editing...
December 4, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29197659/network-based-method-for-mining-novel-hpv-infection-related-genes-using-random-walk-with-restart-algorithm
#20
Liucun Zhu, Fangchu Su, YaoChen Xu, Quan Zou
The human papillomavirus (HPV), a common virus that infects the reproductive tract, may lead to malignant changes within the infection area in certain cases and is directly associated with such cancers as cervical cancer, anal cancer, and vaginal cancer. Identification of novel HPV infection related genes can lead to a better understanding of the specific signal pathways and cellular processes related to HPV infection, providing information for the development of more efficient therapies. In this study, several novel HPV infection related genes were predicted by a computation method based on the known genes involved in HPV infection from HPVbase...
November 29, 2017: Biochimica et Biophysica Acta
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