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Molecular Therapy. Methods & Clinical Development

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https://www.readbyqxmd.com/read/29322065/modeling-anti-hiv-1-hspc-based-gene-therapy-in-humanized-mice-previously-infected-with-hiv-1
#1
Wannisa Khamaikawin, Saki Shimizu, Masakazu Kamata, Ruth Cortado, Yujin Jung, Jennifer Lam, Jing Wen, Patrick Kim, Yiming Xie, Sanggu Kim, Hubert Arokium, Angela P Presson, Irvin S Y Chen, Dong Sung An
Investigations of anti-HIV-1 human hematopoietic stem/progenitor cell (HSPC)-based gene therapy have been performed by HIV-1 challenge after the engraftment of gene-modified HSPCs in humanized mouse models. However, the clinical application of gene therapy is to treat HIV-1-infected patients. Here, we developed a new method to investigate an anti-HIV-1 HSPC-based gene therapy in humanized mice previously infected with HIV-1. First, humanized mice were infected with HIV-1. When plasma viremia reached >107 copies/mL 3 weeks after HIV-1 infection, the mice were myeloablated with busulfan and transplanted with anti-HIV-1 gene-modified CD34+ HSPCs transduced with a lentiviral vector expressing two short hairpin RNAs (shRNAs) against CCR5 and HIV-1 long terminal repeat (LTR), along with human thymus tissue under the kidney capsule...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29255742/engineering-pten-l-for-cell-mediated-delivery
#2
Sylvie J Lavictoire, Alexander Gont, Lisa M Julian, William L Stanford, Caitlyn Vlasschaert, Douglas A Gray, Danny Jomaa, Ian A J Lorimer
The tumor suppressor PTEN is frequently inactivated in glioblastoma. PTEN-L is a long form of PTEN produced by translation from an alternate upstream start codon. Unlike PTEN, PTEN-L has a signal sequence and a tract of six arginine residues that allow PTEN-L to be secreted from cells and be taken up by neighboring cells. This suggests that PTEN-L could be used as a therapeutic to restore PTEN activity. However, effective delivery of therapeutic proteins to treat CNS cancers such as glioblastoma is challenging...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29234687/delivery-of-cr2-fh-using-aav-vector-therapy-as-treatment-strategy-in-the-mouse-model-of-choroidal-neovascularization
#3
Gloriane Schnabolk, Nathaniel Parsons, Elisabeth Obert, Balasubramaniam Annamalai, Cecile Nasarre, Stephen Tomlinson, Alfred S Lewin, Bärbel Rohrer
Complement activation plays a significant role in age-related macular degeneration (AMD) pathogenesis, and polymorphisms interfering with factor H (fH) function, a complement alternative pathway (AP) inhibitor, are associated with increased AMD risk. We have previously validated an AP inhibitor, a fusion protein consisting of a complement receptor 2 fragment linked to the inhibitory domain of fH (CR2-fH) as an efficacious treatment for choroidal neovascularization (CNV) when delivered intravenously. Here we tested an alternative approach of AAV-mediated delivery (AAV5-VMD2-CR2-fH or AAV5-VMD2-mCherry) using subretinal delivery in C57BL/6J mice...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29326962/emerging-issues-in-aav-mediated-in%C3%A2-vivo-gene-therapy
#4
REVIEW
Pasqualina Colella, Giuseppe Ronzitti, Federico Mingozzi
In recent years, the number of clinical trials in which adeno-associated virus (AAV) vectors have been used for in vivo gene transfer has steadily increased. The excellent safety profile, together with the high efficiency of transduction of a broad range of target tissues, has established AAV vectors as the platform of choice for in vivo gene therapy. Successful application of the AAV technology has also been achieved in the clinic for a variety of conditions, including coagulation disorders, inherited blindness, and neurodegenerative diseases, among others...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29276718/a-nonhuman-primate-transplantation-model-to-evaluate-hematopoietic-stem-cell-gene-editing-strategies-for-%C3%AE-hemoglobinopathies
#5
Olivier Humbert, Christopher W Peterson, Zachary K Norgaard, Stefan Radtke, Hans-Peter Kiem
Reactivation of fetal hemoglobin (HbF) is a promising approach for the treatment of β-hemoglobinopathies and the targeting of genes involved in HbF regulation is under intensive investigation. Here, we established a nonhuman primate (NHP) transplantation model to evaluate hematopoietic stem cell (HSC)-based gene editing strategies aimed at reactivating HbF. We first characterized the transient HbF induction to autologous HSC transplantation in pigtailed macaques, which was comparable in duration and amplitude to that of human patients...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29255741/a-combined-in%C3%A2-vivo-hsc-transduction-selection-approach-results-in-efficient-and-stable-gene-expression-in-peripheral-blood-cells-in-mice
#6
Hongjie Wang, Maximilian Richter, Nikoletta Psatha, Chang Li, Jiho Kim, Jing Liu, Anja Ehrhardt, Susan K Nilsson, Benjamin Cao, Donna Palmer, Philip Ng, Zsuzsanna Izsvák, Kevin G Haworth, Hans-Peter Kiem, Thalia Papayannopoulou, André Lieber
We recently reported on an in vivo hematopoietic stem cell (HSC) gene therapy approach. It involves the subcutaneous injections of G-CSF/AMD3100 to mobilize HSCs from the bone marrow into the peripheral blood stream and the intravenous injection of an integrating helper-dependent adenovirus vector system. HSCs transduced in the periphery homed back to the bone marrow, where they persisted long-term. However, high transgene marking rates found in primitive bone marrow HSCs were not reflected in peripheral blood cells...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29159202/a-humoral-immune-response-alters-the-distribution-of-enzyme-replacement-therapy-in-murine-mucopolysaccharidosis-type-i
#7
Steven Q Le, Shih-Hsin Kan, Don Clarke, Valentina Sanghez, Martin Egeland, Kristen N Vondrak, Terence M Doherty, Moin U Vera, Michelina Iacovino, Jonathan D Cooper, Mark S Sands, Patricia I Dickson
Antibodies against recombinant proteins can significantly reduce their effectiveness in unanticipated ways. We evaluated the humoral response of mice with the lysosomal storage disease mucopolysaccharidosis type I treated with weekly intravenous recombinant human alpha-l-iduronidase (rhIDU). Unlike patients, the majority of whom develop antibodies to recombinant human alpha-l-iduronidase, only approximately half of the treated mice developed antibodies against recombinant human alpha-l-iduronidase and levels were low...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29159201/interactions-between-retroviruses-and-the-host-cell-genome
#8
REVIEW
Valentina Poletti, Fulvio Mavilio
Replication-defective retroviral vectors have been used for more than 25 years as a tool for efficient and stable insertion of therapeutic transgenes in human cells. Patients suffering from severe genetic diseases have been successfully treated by transplantation of autologous hematopoietic stem-progenitor cells (HSPCs) transduced with retroviral vectors, and the first of this class of therapies, Strimvelis, has recently received market authorization in Europe. Some clinical trials, however, resulted in severe adverse events caused by vector-induced proto-oncogene activation, which showed that retroviral vectors may retain a genotoxic potential associated to proviral integration in the human genome...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29159200/analyzing-the-genotoxicity-of-retroviral-vectors-in-hematopoietic-cell-gene-therapy
#9
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/29034262/detection-of-replication-competent-lentivirus-using-a-qpcr-assay-for-vsv-g
#10
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/29296626/a-rabbit-model-for-testing-helper-dependent-adenovirus-mediated-gene-therapy-for-vein-graft-atherosclerosis
#11
Lianxiang Bi, Bradley K Wacker, Emma Bueren, Ervin Ham, Nagadhara Dronadula, David A Dichek
Coronary artery bypass vein grafts are a mainstay of therapy for human atherosclerosis. Unfortunately, the long-term patency of vein grafts is limited by accelerated atherosclerosis. Gene therapy, directed at the vein graft wall, is a promising approach for preventing vein graft atherosclerosis. Because helper-dependent adenovirus (HDAd) efficiently transduces grafted veins and confers long-term transgene expression, HDAd is an excellent candidate for delivery of vein graft-targeted gene therapy. We developed a model of vein graft atherosclerosis in fat-fed rabbits and demonstrated long-term (≥20 weeks) persistence of HDAd genomes after graft transduction...
December 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29296625/molecular-therapy-of-melanocortin-4-receptor-obesity-by-an-autoregulatory-bdnf-vector
#12
Jason J Siu, Nicholas J Queen, Xianglan Liu, Wei Huang, Travis McMurphy, Lei Cao
Mutations in the melanocortin-4-receptor (MC4R) comprise the most common monogenic form of severe early-onset obesity, and conventional treatments are either ineffective long-term or contraindicated. Immediately downstream of MC4R-in the pathway for regulating energy balance-is brain-derived neurotrophic factor (BDNF). Our previous studies show that adeno-associated virus (AAV)-mediated hypothalamic BDNF gene transfer alleviates obesity and diabetes in both diet-induced and genetic models. To facilitate clinical translation, we developed a built-in autoregulatory system to control therapeutic gene expression mimicking the body's natural feedback systems...
December 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29255740/a-robust-system-for-production-of-superabundant-vp1-recombinant-aav-vectors
#13
Qizhao Wang, Zhongren Wu, Junping Zhang, Jenni Firrman, Hongying Wei, Zhengjing Zhuang, LinShu Liu, Linqing Miao, Yang Hu, Dong Li, Yong Diao, Weidong Xiao
Recombinant adeno-associated viral (rAAV) vectors have been widely used in human gene therapy. One major impediment to its broad application is the inability to produce high-quality vectors in mass quantity. Here, an efficient and scalable suspension cell culture system for the production of rAAV vectors is described. In this system, the AAV trans factors, Rep78, Rep52, VP1, VP2, and VP3, were stably integrated into a single vaccinia virus carrier by maximizing the use of alternative codons between genes with identical amino acids, and the cis rAAV genome was carried by an E1/E3 gene-deleted adenovirus...
December 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29201936/targeted-cell-to-cell-delivery-of-protein-payloads-via-the-granzyme-perforin-pathway
#14
Daniel J Woodsworth, Lisa Dreolini, Libin Abraham, Robert A Holt
There is great potential for engineering cellular therapeutics by repurposing biological systems. Here, we report utilization of the granzyme-perforin pathway of cytotoxic lymphocytes as a cell-to-cell protein delivery module. We designed and constructed granzyme B-derived chaperone molecules fused to a fluorescent protein payload and expressed these constructs in natural killer (NK) cells. Using confocal microscopy and flow cytometry, we investigated the co-localization of the chaperones with lytic granules and the chaperone-mediated transfer of the fluorescent protein payload from NK to target cells in co-culture experiments...
December 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29159199/dna-mediated-gene-therapy-in-a-mouse-model-of-limb-girdle-muscular-dystrophy-2b
#15
Julia Ma, Christophe Pichavant, Haley du Bois, Mital Bhakta, Michele P Calos
Mutations in the gene for dysferlin cause a degenerative disorder of skeletal muscle known as limb girdle muscular dystrophy 2B. To achieve gene delivery of plasmids encoding dysferlin to hind limb muscles of dysferlin knockout mice, we used a vascular injection method that perfused naked plasmid DNA into all major muscle groups of the hind limb. We monitored delivery by luciferase live imaging and western blot, confirming strong dysferlin expression that persisted over the 3-month time course of the experiment...
December 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29085848/rapid-generation-of-multiple-loci-engineered-marker-free-poxvirus-and-characterization-of-a-clinical-grade-oncolytic-vaccinia-virus
#16
Zong Sheng Guo, Zuqiang Liu, Magesh Sathaiah, Jiahu Wang, Roshni Ravindranathan, Eun Kim, Shaohua Huang, Thomas W Kenniston, John C Bell, Herbert J Zeh, Lisa H Butterfield, Andrea Gambotto, David L Bartlett
Recombinant poxviruses, utilized as vaccine vectors and oncolytic viruses, often require manipulation at multiple genetic loci in the viral genome. It is essential for viral vectors to possess no adventitious mutations and no (antibiotic) selection marker in the final product for human patients in order to comply with the guidance from the regulatory agencies. Rintoul et al. have previously developed a selectable and excisable marker (SEM) system for the rapid generation of recombinant vaccinia virus. In the current study, we describe an improved methodology for rapid creation and selection of recombinant poxviruses with multiple genetic manipulations solely based on expression of a fluorescent protein and with no requirement for drug selection that can lead to cellular stress and the risk of adventitious mutations throughout the viral genome...
December 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29057281/atg5-flox-derived-autophagy-deficient-model-of-pompe-disease-does-it-tell-the-whole-story
#17
REVIEW
Jeong-A Lim, Hossein Zare, Rosa Puertollano, Nina Raben
No abstract text is available yet for this article.
December 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29034261/in%C3%A2-vivo-production-of-monoclonal-antibodies-by-gene-transfer-via-electroporation-protects-against-lethal-influenza-and-ebola-infections
#18
Chasity D Andrews, Yang Luo, Ming Sun, Jian Yu, Arthur J Goff, Pamela J Glass, Neal N Padte, Yaoxing Huang, David D Ho
Monoclonal antibodies (mAbs) have wide clinical utility, but global access is limited by high costs and impracticalities associated with repeated passive administration. Here, we describe an optimized electroporation-based DNA gene transfer platform technology that can be utilized for production of functional mAbs in vivo, with the potential to reduce costs and administration burdens. We demonstrate that multiple mAbs can be simultaneously expressed at protective concentrations for a protracted period of time using DNA doses and electroporation conditions that are feasible clinically...
December 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29034260/clodronate-improves-survival-of-transplanted-hoxb8-myeloid-progenitors-with-constitutively-active-gmcsfr-in-immunocompetent-mice
#19
Simon Lee, Saul Kivimäe, Francis C Szoka
New methods to produce large numbers of myeloid progenitor cells, precursors to macrophages (MΦs), by maintaining Hoxb8 transcription factor activity(1) has reinvigorated interest in MΦ cell therapies. We generated Hoxb8-dependent myeloid progenitors (HDPs) by transducing lineage-negative bone marrow cells with a constitutively expressed Hoxb8 flanked by loxP. HDPs proliferate indefinitely and differentiate into MΦ when Hoxb8 is removed by a tamoxifen-inducible Cre. We genetically modified HDPs with a constitutively active GMCSF receptor and the tamoxifen-induced transcription factor IRF8, which we have termed "HDP-on...
December 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29018836/one-step-fabrication-of-bone-morphogenetic-protein-2-gene-activated-porous-poly-l-lactide-scaffold-for-bone-induction
#20
Jingwen Xue, Hang Lin, Allison Bean, Ying Tang, Jian Tan, Rocky S Tuan, Bing Wang
Bone morphogenetic protein 2 (BMP2) is an efficacious inducer for the osteogenesis of mesenchymal stem cells (MSCs). Conventional applications of BMP2 have involved either the direct incorporation of BMP2 protein or ex vivo BMP2 gene transfer into stem cells prior to their transplantation. These approaches are able to promote bone formation to some extent; however, they are hampered by either the lack of stability and sustainability of BMP2 protein or the time-consuming and cost-prohibitive in vitro cell culture procedure...
December 15, 2017: Molecular Therapy. Methods & Clinical Development
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