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Lentivirus vector therapy

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https://www.readbyqxmd.com/read/29221804/the-impact-of-the-cd9-tetraspanin-on-lentivirus-infectivity-and-exosome-secretion
#1
Kai O Böker, Nicolas Lemus-Diaz, Rafael Rinaldi Ferreira, Lara Schiller, Stefan Schneider, Jens Gruber
Efficient transduction tools are a hallmark for both research and therapy development. Here, we introduce new insights into the generation of lentiviral vectors with improved performance by utilizing producer cells with increased production rates of extracellular vesicles through CD9 overexpression. Most human cells secrete small vesicles from their surface (microvesicles) or intraluminal endosome-derived membranes (exosomes). In particular, enhanced levels of the tetraspanin CD9 result in significantly increased numbers of extracellular vesicles with exosome-like features that were secreted from four different human cell lines...
November 16, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29212357/manufacture-of-third-generation-lentivirus-for-preclinical-use-with-process-development-considerations-for-translation-to-good-manufacturing-practice-gmp
#2
Carolina Gándara, Valerie Affleck, Elizabeth Ann Stoll
Lentiviral vectors are used in laboratories around the world for in vivo and ex vivo delivery of gene therapies, and increasingly used for clinical investigation as well as preclinical applications. The third-generation lentiviral vector system has many advantages, including high packaging capacity, stable gene expression in both dividing and post-mitotic cells, and low immunogenicity in the recipient organism. Yet the manufacture of these vectors is challenging, especially at high titres required for direct use in vivo, and further challenges are presented by the process of translating preclinical gene therapies toward manufacture of products for clinical investigation...
December 6, 2017: Human Gene Therapy Methods
https://www.readbyqxmd.com/read/29203150/retroviral-and-lentiviral-safety-analysis-of-gene-modified-t-cell-products-and-infused-hiv-and-oncology-patients
#3
Katherine T Marcucci, Julie K Jadlowsky, Wei-Ting Hwang, Megan Suhoski-Davis, Vanessa E Gonzalez, Irina Kulikovskaya, Minnal Gupta, Simon F Lacey, Gabriela Plesa, Anne Chew, J Joseph Melenhorst, Bruce L Levine, Carl H June
Replication-competent retrovirus/lentivirus (RCR/L) and insertional oncogenesis are potential safety risks with integrating viruses in gene-modified cell therapies. As such, the Food and Drug Administration guidances outline RCR/L-monitoring methods throughout the entire gene therapy treatment cycle. We present data for 17 vector lots, 375 manufactured T cell products, and 308 patients post-infusion across both HIV and oncology indications, showing no evidence of RCR/L. Given our data, a Poisson probability model estimates that a single patient, or a group of patients, would need to be followed for at least 52...
October 20, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29188505/development-of-multigenic-lentiviral-vectors-for-cell-specific-expression-of-antiangiogenic-mirnas-and-protein-factors
#4
Anne Louise Askou, Thomas J Corydon
Generation of lentivirus (LV)-based vectors holding multiple gene cassettes for coexpression of several therapeutic factors provides potent tools in both gene delivery studies as well as in gene therapy. Here we describe the development of such multigenic LV gene delivery vectors enabling cell-specific coexpression of antiangiogenic microRNA (miRNA) and protein factors and, if preferred, a fluorescent reporter, from RNApol(II)-driven expression cassettes orientated in a back-to-back fashion. This configuration may contribute to the development of new combination therapies for amelioration of diseases involving intraocular neovascularization including exudative age-related macular degeneration (AMD)...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29179571/the-role-of-basal-cells-in-producing-persistent-lentivirus-mediated-airway-gene-expression
#5
Nigel R Farrow, Martin Donnelley, Patricia Cmielewski, Eugene Roscioli, Nathan Rout-Pitt, Chantelle McIntyre, Ivan Bertoncello, David Parsons
RATIONALE: Cystic Fibrosis (CF) lung disease is an ideal candidate for a genetic therapy. We have previously shown that pre-conditioning with lysophosphatidylcholine (LPC) prior to lentiviral (LV) vector delivery results in long-term in vivo gene expression in the airway epithelium of CF mice. We hypothesise that this outcome is largely due to transduction of airway basal cells that in turn pass the transgene onto their progeny. OBJECTIVES: The aim of these studies was to confirm if the in vivo delivery of a HIV-1 VSV-G pseudotyped LV vector following LPC airway conditioning results in transduction of mouse airway basal cells in situ and if the transgene is passed onto their progeny...
November 27, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/29159200/analyzing-the-genotoxicity-of-retroviral-vectors-in-hematopoietic-cell-gene-therapy
#6
REVIEW
Luca Biasco, Michael Rothe, Hildegard Büning, Axel Schambach
Retroviral vectors, including those derived from gammaretroviruses and lentiviruses, have found their way into the clinical arena and demonstrated remarkable efficacy for the treatment of immunodeficiencies, leukodystrophies, and globinopathies. Despite these successes, gene therapy unfortunately also has had to face severe adverse events in the form of leukemias and myelodysplastic syndromes, related to the semi-random vector integration into the host cell genome that caused deregulation of neighboring proto-oncogenes...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29150004/dynamics-of-indel-profiles-induced-by-various-crispr-cas9-delivery-methods
#7
Michael Kosicki, Sandeep S Rajan, Flaminia C Lorenzetti, Hans H Wandall, Yoshiki Narimatsu, Emmanouil Metzakopian, Eric P Bennett
The introduction of CRISPR/Cas9 gene editing in mammalian cells is a scientific breakthrough, which has greatly affected basic research and gene therapy. The simplicity and general access to CRISPR/Cas9 reagents has in an unprecedented manner "democratized" gene targeting in biomedical research, enabling genetic engineering of any gene in any cell, tissue, organ, and organism. The ability for fast, precise, and efficient profiling of the double-stranded break induced insertions and deletions (indels), mediated by any of the available programmable nucleases, is paramount to any given gene targeting approach...
2017: Progress in Molecular Biology and Translational Science
https://www.readbyqxmd.com/read/29130351/the-gene-therapy-resource-program-a-decade-of-dedication-to-translational-research-by-the-national-heart-lung-and-blood-institute
#8
Terence R Flotte, Eric Daniels, Janet Benson, Jenee M Bevett-Rose, Kenneth Cornetta, Margaret Diggins, Julie Johnston, Susan Sepelak, Johannes Van Der Loo, James M Wilson, Cheryl L McDonald
Over a ten-year period, the Gene Therapy Resource Program (GTRP) of the National Heart Lung and Blood Institute (NHLBI) has provided a set of core services to investigators to facilitate the clinical translation of gene therapy. These services have included a preclinical (research-grade) vector production core; current Good Manufacturing Practice (cGMP) clinical-grade vector cores for recombinant adeno-associated virus (rAAV) and lentivirus vectors; a pharmacology and toxicology core; and a coordinating center to manage program logistics and to provide regulatory and financial support to early phase clinical trials...
November 12, 2017: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29105567/in-vivo-survival-of-human-endometrial-mesenchymal-stem-cells-transplanted-under-the-kidney-capsule-of-immunocompromised-mice
#9
Shanti Gurung, James A Deane, Saeedeh Darzi, Jerome A Werkmeister, Caroline E Gargett
Human endometrial mesenchymal stem cells (eMSCs) are a well-characterised adult stem cell type with potential for use in regenerative medicine or cell-therapy. As a proof of principle, we demonstrated that eMSCs promoted wound healing by reducing the inflammatory response through a paracrine action in a subcutaneous rat model of wound repair. However, an efficient protocol for culturing eMSCs in the undifferentiated state and a reliable method of labelling them for cell tracking were lacking. Here, we investigated the use of a lentiviral vector containing the mCherry fluorescent reporter gene to transduce and label eMSCs following in vitro culturing in A83-01-containing medium, and different methods of tracing the labelled cells following transplantation under the kidney capsule of immunocompromised NSG mice...
November 4, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/29077949/incorporation-of-aptamers-in-the-terminal-loop-of-shrnas-yields-an-effective-and-novel-combinatorial-targeting-strategy
#10
Ka Ming Pang, Daniela Castanotto, Haitang Li, Lisa Scherer, John J Rossi
Gene therapy by engineering patient's own blood cells to confer HIV resistance can potentially lead to a functional cure for AIDS. Toward this goal, we have previously developed an anti-HIV lentivirus vector that deploys a combination of shRNA, ribozyme and RNA decoy. To further improve this therapeutic vector against viral escape, we sought an additional reagent to target HIV integrase. Here, we report the development of a new strategy for selection and expression of aptamer for gene therapy. We developed a SELEX protocol (multi-tag SELEX) for selecting RNA aptamers against proteins with low solubility or stability, such as integrase...
October 25, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29057663/gene-therapy-for-inherited-retinal-and-optic-nerve-degenerations
#11
Nicholas A Moore, Nuria Morral, Thomas A Ciulla, Peter Bracha
The eye is a target for investigational gene therapy due to the monogenic nature of many inherited retinal and optic nerve degenerations (IRD), its accessibility, tight blood-ocular barrier, the ability to non-invasively monitor for functional and anatomic outcomes, as well as its relative immune privileged state.Vectors currently used in IRD clinical trials include adeno-associated virus (AAV), small single-stranded DNA viruses, and lentivirus, RNA viruses of the retrovirus family. Both can transduce non-dividing cells, but AAV are non-integrating, while lentivirus integrate into the host cell genome, and have a larger transgene capacity...
October 23, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/29046446/foamy-virus-vector-carries-a-strong-insulator-in-its-long-terminal-repeat-which-reduces-its-genotoxic-potential
#12
Michael A Goodman, Paritha I Arumugam, Devin M Pillis, Anastacia Loberg, Md Nasimuzzaman, Danielle Lynn, Johannes C M van der Loo, Phillip J Dexheimer, Mehdi Keddache, Thomas R Bauer, Dennis D Hickstein, David W Russell, Punam Malik
Strong viral enhancers in γ-retrovirus vectors have caused cellular proto-oncogene activation and leukemia, necessitating use of cellular promoters in 'enhancer-less' self-inactivating integrating vectors. However, cellular promoters result in relatively low transgene expression, often leading to inadequate disease correction. Vectors derived from foamy virus, a nonpathogenic retrovirus, show higher preference for non-genic integrations than γ-retroviruses/lentiviruses and preferential integration near transcriptional start sites, like γ-retroviruses...
October 18, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29034262/detection-of-replication-competent-lentivirus-using-a-qpcr-assay-for-vsv-g
#13
Lindsey M Skrdlant, Randall J Armstrong, Brett M Keidaisch, Mario F Lorente, David L DiGiusto
Lentiviral vectors are a common tool used to introduce new and corrected genes into cell therapy products for treatment of human diseases. Although lentiviral vectors are ideal for delivery and stable integration of genes of interest into the host cell genome, they potentially pose risks to human health, such as integration-mediated transformation and generation of a replication competent lentivirus (RCL) capable of infecting non-target cells. In consideration of the latter risk, all cell-based products modified by lentiviral vectors and intended for patient use must be tested for RCL prior to treatment of the patient...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29017974/vectofusin-1-a-potent-peptidic-enhancer-of-viral-gene-transfer-forms-ph-dependent-%C3%AE-helical-nanofibrils-concentrating-viral-particles
#14
Louic S Vermeer, Loic Hamon, Alicia Schirer, Michel Schoup, Jérémie Cosette, Saliha Majdoul, David Pastré, Daniel Stockholm, Nathalie Holic, Petra Hellwig, Anne Galy, David Fenard, Burkhard Bechinger
Gene transfer using lentiviral vectors has therapeutic applications spanning from monogenic and infectious diseases to cancer. Such gene therapy has to be improved by enhancing the levels of viral infection of target cells and/or reducing the amount of lentivirus for greater safety and reduced costs. Vectofusin-1, a recently developed cationic amphipathic peptide with a pronounced capacity to enhance such viral transduction, strongly promotes the entry of several retroviral pseudotypes into target cells when added to the culture medium...
December 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28982327/comparative-study-of-adeno-associated-virus-adenovirus-baculovirus-and-lentivirus-vectors-for-gene-therapy-of-the-eyes
#15
Giedrius Kalesnykas, Emmi Kokki, Laura Alasaarela, Hanna P Lesch, Timo Tuulos, Kati Kinnunen, Hannu Uusitalo, Kari Airenne, Seppo Ylä-Herttuala
Background The eye possesses unique anatomical features that make it a valuable target for gene therapy applications. Objective The aim of the current study was to compare transduction efficiency, safety and biodistribution of four viral vectors following intravitreal injection. Method Adenovirus (AdV), adeno-associated virus (AAV), baculovirus (BV) and lentivirus (LV) vectors encoding green fluorescent protein (GFP) were injected bilaterally intravitreally into adult C57BL/6OlaHsd mice. Control mice received saline...
October 3, 2017: Current Gene Therapy
https://www.readbyqxmd.com/read/28970045/absence-of-replication-competent-lentivirus-in-the-clinic-analysis-of-infused-t-cell-products
#16
Kenneth Cornetta, Lisa Duffy, Cameron J Turtle, Michael Jensen, Stephen Forman, Gwendolyn Binder-Scholl, Terry Fry, Anne Chew, David G Maloney, Carl H June
Exposure to replication-competent lentivirus (RCL) is a theoretical safety concern for individuals treated with lentiviral gene therapy. For certain ex vivo gene therapy applications, including cancer immunotherapy trials, RCL detection assays are used to screen the vector product as well as the vector-transduced cells. In this study, we reviewed T cell products screened for RCL using methodology developed in the National Gene Vector Biorepository. All trials utilized third-generation lentiviral vectors produced by transient transfection...
September 12, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28962641/overexpression-of-hypoxia-inducible-factor-1-alpha-improves-immunomodulation-by-dental-mesenchymal-stem-cells
#17
Victor G Martinez, Imelda Ontoria-Oviedo, Carolina P Ricardo, Sian E Harding, Rosa Sacedon, Alberto Varas, Agustin Zapata, Pilar Sepulveda, Angeles Vicente
BACKGROUND: Human dental mesenchymal stem cells (MSCs) are considered as highly accessible and attractive MSCs for use in regenerative medicine, yet some of their features are not as well characterized as other MSCs. Hypoxia-preconditioning and hypoxia-inducible factor 1 (HIF-1) alpha overexpression significantly improves MSC therapeutics, but the mechanisms involved are not fully understood. In the present study, we characterize immunomodulatory properties of dental MSCs and determine changes in their ability to modulate adaptive and innate immune populations after HIF-1 alpha overexpression...
September 29, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/28941328/inducing-indel-mutation-in-the-sox6-gene-by-zinc-finger-nuclease-for-gamma-reactivation-an-approach-towards-gene-therapy-of-beta-thalassemia
#18
Mehran Modares, Laleh Shariati, Zahra Hejazi, Mansoureh Shahbazi, Mohammad Amin Tabatabaiefar, Hossein Khanahmad
β-thalassemia is a common autosomal recessive disorder characterized by a deficiency in the synthesis of β-chains.Evidences show that increased HbF levels improve the symptoms in patients with β-thalassemia or sickle cell anemia. In this study, ZFN technology was applied to induce a mutation in the binding domain region of SOX6 to reactivate γ-globin expression. The sequences coding for ZFP arrays were designed and sub cloned in TDH plus as a transfer vector. The ZFN expression was confirmed using Western blot analysis...
September 23, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28941274/advancements-in-the-design-and-scalable-production-of-viral-gene-transfer-vectors
#19
REVIEW
David Sharon, Amine Kamen
The last 10 years have seen a rapid expansion in the use of viral gene transfer vectors, with approved therapies and late stage clinical trials underway for the treatment of genetic disorders, and multiple forms of cancer, as well as prevention of infectious diseases through vaccination. With this increased interest and widespread adoption of viral vectors by clinicians and biopharmaceutical industries, there is an imperative to engineer safer and more efficacious vectors, and develop robust, scalable and cost-effective production platforms for industrialization...
September 23, 2017: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/28895846/in%C3%A2-vivo-hematopoietic-stem-cell-transduction
#20
REVIEW
Maximilian Richter, Daniel Stone, Carol Miao, Olivier Humbert, Hans-Peter Kiem, Thalia Papayannopoulou, André Lieber
Current protocols for hematopoietic stem cell (HSC) gene therapy, involving the transplantation of ex vivo lentivirus vector-transduced HSCs into myeloablated recipients, are complex and not without risk for the patient. In vivo HSC gene therapy can be achieved by the direct modification of HSCs in the bone marrow after intraosseous injection of gene delivery vectors. A recently developed approach involves the mobilization of HSCs from the bone marrow into peripheral the blood circulation, intravenous vector injection, and re-engraftment of genetically modified HSCs in the bone marrow...
October 2017: Hematology/oncology Clinics of North America
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