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Molecular Therapy: the Journal of the American Society of Gene Therapy

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https://www.readbyqxmd.com/read/28527723/activation-of-nrf2-signaling-augments-vesicular-stomatitis-virus-oncolysis-via-autophagy-driven-suppression-of-antiviral-immunity
#1
David Olagnier, Rassin R Lababidi, Samar Bel Hadj, Alexandre Sze, Yiliu Liu, Sharadha Dayalan Naidu, Matteo Ferrari, Yuan Jiang, Cindy Chiang, Vladimir Beljanski, Marie-Line Goulet, Elena V Knatko, Albena T Dinkova-Kostova, John Hiscott, Rongtuan Lin
Oncolytic viruses (OVs) offer a promising therapeutic approach to treat multiple types of cancer. In this study, we show that the manipulation of the antioxidant network via transcription factor Nrf2 augments vesicular stomatitis virus Δ51 (VSVΔ51) replication and sensitizes cancer cells to viral oncolysis. Activation of Nrf2 signaling by the antioxidant compound sulforaphane (SFN) leads to enhanced VSVΔ51 spread in OV-resistant cancer cells and improves the therapeutic outcome in different murine syngeneic and xenograft tumor models...
May 17, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28527722/crispr-cas9-mediated-ccr5-ablation-in-human-hematopoietic-stem-progenitor-cells-confers-hiv-1-resistance-in%C3%A2-vivo
#2
Lei Xu, Huan Yang, Yang Gao, Zeyu Chen, Liangfu Xie, Yulin Liu, Ying Liu, Xiaobao Wang, Hanwei Li, Weifeng Lai, Yuan He, Anzhi Yao, Liying Ma, Yiming Shao, Bin Zhang, Chengyan Wang, Hu Chen, Hongkui Deng
Transplantation of hematopoietic stem cells (HSCs) with a naturally occurring CCR5 mutation confers a loss of detectable HIV-1 in the patient, making ablation of the CCR5 gene in HSCs an ideal therapy for an HIV-1 cure. Although CCR5 disruption has been attempted in CD4(+) T cells and hematopoietic stem/progenitor cells (HSPCs), efficient gene editing with high specificity and long-term therapeutic potential remains a major challenge for clinical translation. Here, we established a CRISPR/Cas9 gene editing system in human CD34(+) HSPCs and achieved efficient CCR5 ablation evaluated in long-term reconstituted NOD/Prkdc(scid)/IL-2Rγ(null) mice...
May 17, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28522034/alpha-synuclein-mrna-is-not-increased
#3
LETTER
Xiaomin Su, D Luke Fischer, Xin Li, Krystof Bankiewicz, Caryl E Sortwell, Howard J Federoff
No abstract text is available yet for this article.
May 15, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28506594/fingolimod-and-teriflunomide-attenuate-neurodegeneration-in-mouse-models-of-neuronal-ceroid-lipofuscinosis
#4
Janos Groh, Kristina Berve, Rudolf Martini
CLN diseases are rare lysosomal storage diseases characterized by progressive axonal degeneration and neuron loss in the CNS, manifesting in disability, blindness, and premature death. We have previously demonstrated that, in animal models of infantile and juvenile forms of CLN disease (CLN1 and CLN3, respectively), secondary neuroinflammation in the CNS substantially amplifies neural damage, opening the possibility that immunomodulatory treatment might improve disease outcome. First, we recapitulated the inflammatory phenotype, originally seen in mice in autopsies of CLN patients...
May 13, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28506593/a-rational-strategy-for-reducing-on-target-off-tumor-effects-of-cd38-chimeric-antigen-receptors-by-affinity-optimization
#5
Esther Drent, Maria Themeli, Renée Poels, Regina de Jong-Korlaar, Huipin Yuan, Joost de Bruijn, Anton C M Martens, Sonja Zweegman, Niels W C J van de Donk, Richard W J Groen, Henk M Lokhorst, Tuna Mutis
Chimeric antigen receptors (CARs) can effectively redirect cytotoxic T cells toward highly expressed surface antigens on tumor cells. The low expression of several tumor-associated antigens (TAAs) on normal tissues, however, hinders their safe targeting by CAR T cells due to on-target/off-tumor effects. Using the multiple myeloma (MM)-associated CD38 antigen as a model system, here, we present a rational approach for effective and tumor-selective targeting of such TAAs. Using "light-chain exchange" technology, we combined the heavy chains of two high-affinity CD38 antibodies with 176 germline light chains and generated ∼124 new antibodies with 10- to >1,000-fold lower affinities to CD38...
May 13, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28502471/reference-standards-for-gene-and-cell-therapy-products
#6
EDITORIAL
Boro Dropulić
No abstract text is available yet for this article.
May 10, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28502470/antitumoral-cascade-targeting-ligand-for-il-6-receptor-mediated-gene-delivery-to-glioma
#7
Shanshan Wang, Sören Reinhard, Chengyi Li, Min Qian, Huiling Jiang, Yilin Du, Ulrich Lächelt, Weiyue Lu, Ernst Wagner, Rongqin Huang
The effective treatment of glioma is largely hindered by the poor transfer of drug delivery systems across the blood-brain barrier (BBB) and the difficulty in distinguishing healthy and tumorous cells. In this work, for the first time, an interleukin-6 receptor binding I6P7 peptide was exploited as a cascade-targeting ligand in combination with a succinoyl tetraethylene pentamine (Stp)-histidine oligomer-based nonviral gene delivery system (I6P7-Stp-His/DNA). The I6P7 peptide provides multiple functions, including the cascade-targeting potential represented by a combined BBB-crossing and subsequent glioma-targeting ability, as well as a direct tumor-inhibiting effect...
May 10, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28502469/hepatocyte-growth-factor-suppresses-inflammation-and-promotes-epithelium-repair-in-corneal-injury
#8
Masahiro Omoto, Kunal Suri, Afsaneh Amouzegar, Mingshun Li, Kishore R Katikireddy, Sharad K Mittal, Sunil K Chauhan
Corneal injuries are among the major causes of ocular morbidity and vision impairment. Optimal epithelial wound healing is critical for the integrity and transparency of the cornea after injury. Hepatocyte growth factor (HGF) is a mitogen and motility factor that primarily regulates epithelial cell function. Herein, we investigate the effect of HGF on proliferation of corneal epithelial cells (CECs) in inflamed conditions both in vitro and in vivo. We demonstrate that HGF not only promotes CEC proliferation in homeostatic conditions but also reverses the anti-proliferative effect of the inflammatory environment on these cells...
May 10, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28499750/ticket-to-ride-targeting-proteins-to-exosomes-for-brain-delivery
#9
Eva-Maria Krämer-Albers
No abstract text is available yet for this article.
May 10, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28528817/tracing-and-characterizing-the-development-of-transplanted-female-germline-stem-cells-in%C3%A2-vivo
#10
Changqing Wu, Bo Xu, Xiaoyong Li, Wenzhi Ma, Ping Zhang, Xuejin Chen, Ji Wu
It has long been believed that most female mammalian species lose the ability to generate oocytes in postnatal ovaries. Recent evidence has demonstrated the isolation and culture of female germline stem cells (FGSCs) from adult mice and humans. However, the process and mechanisms of FGSC differentiation in vivo following transplantation have not yet been studied. Here, we isolated and characterized FGSCs from a single EGFP-transgenic mouse, and traced the development and behavior of transplanted FGSCs (F-TFs) in vivo...
May 6, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28487115/lncrna-hoxd-as1-regulates-proliferation-and-chemo-resistance-of-castration-resistant-prostate-cancer-via-recruiting-wdr5
#11
Peng Gu, Xu Chen, Ruihui Xie, Jinli Han, Weibin Xie, Bo Wang, Wen Dong, Changhao Chen, Meihua Yang, Junyi Jiang, Ziyue Chen, Jian Huang, Tianxin Lin
Castration-resistant prostate cancer (CRPC) that occurs after the failure of androgen deprivation therapy is the leading cause of deaths in prostate cancer patients. Thus, there is an obvious and urgent need to fully understand the mechanism of CRPC and discover novel therapeutic targets. Long noncoding RNAs (lncRNAs) are crucial regulators in many human cancers, yet their potential roles and molecular mechanisms in CRPC are poorly understood. In this study, we discovered that an lncRNA HOXD-AS1 is highly expressed in CRPC cells and correlated closely with Gleason score, T stage, lymph nodes metastasis, and progression-free survival...
May 6, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28479234/controlled-delivery-of-single-or-multiple-antigens-in-tolerogenic-nanoparticles-using-peptide-polymer-bioconjugates
#12
Ryan M Pearson, Liam M Casey, Kevin R Hughes, Leon Z Wang, Madeleine G North, Daniel R Getts, Stephen D Miller, Lonnie D Shea
Polymeric nanoparticles (NPs) have demonstrated their potential to induce antigen (Ag)-specific immunological tolerance in multiple immune models and are at various stages of commercial development. Association of Ag with NPs is typically achieved through surface coupling or encapsulation methods. However, these methods have limitations that include high polydispersity, uncontrollable Ag loading and release, and possible immunogenicity. Here, using antigenic peptides conjugated to poly(lactide-co-glycolide), we developed Ag-polymer conjugate NPs (acNPs) with modular loading of single or multiple Ags, negligible burst release, and minimally exposed surface Ag...
May 4, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28479046/a-triple-fluorophore-labeled-nucleic-acid-ph-nanosensor-to-investigate-non-viral-gene-delivery
#13
David R Wilson, Denis Routkevitch, Yuan Rui, Arman Mosenia, Karl J Wahlin, Alfredo Quinones-Hinojosa, Donald J Zack, Jordan J Green
There is a need for new tools to better quantify intracellular delivery barriers in high-throughput and high-content ways. Here, we synthesized a triple-fluorophore-labeled nucleic acid pH nanosensor for measuring intracellular pH of exogenous DNA at specific time points in a high-throughput manner by flow cytometry following non-viral transfection. By including two pH-sensitive fluorophores and one pH-insensitive fluorophore in the nanosensor, detection of pH was possible over the full physiological range...
May 3, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28479045/balance-of-anti-cd123-chimeric-antigen-receptor-binding-affinity-and-density-for-the-targeting-of-acute-myeloid-leukemia
#14
Silvia Arcangeli, Maria Caterina Rotiroti, Marco Bardelli, Luca Simonelli, Chiara Francesca Magnani, Andrea Biondi, Ettore Biagi, Sarah Tettamanti, Luca Varani
Chimeric antigen receptor (CAR)-redirected T lymphocytes are a promising immunotherapeutic approach and object of pre-clinical evaluation for the treatment of acute myeloid leukemia (AML). We developed a CAR against CD123, overexpressed on AML blasts and leukemic stem cells. However, potential recognition of low CD123-positive healthy tissues, through the on-target, off-tumor effect, limits safe clinical employment of CAR-redirected T cells. Therefore, we evaluated the effect of context-dependent variables capable of modulating CAR T cell functional profiles, such as CAR binding affinity, CAR expression, and target antigen density...
May 3, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28457664/in%C3%A2-vivo-delivery-and-therapeutic-effects-of-a-microrna-on-colorectal-liver-metastases
#15
Go Oshima, Nining Guo, Chunbai He, Melinda E Stack, Christopher Poon, Abhineet Uppal, Sean C Wightman, Akash Parekh, Kinga B Skowron, Mitchell C Posner, Wenbin Lin, Nikolai N Khodarev, Ralph R Weichselbaum
Multiple therapeutic agents are typically used in concert to effectively control metastatic tumors. Recently, we described microRNAs that are associated with the oligometastatic state, in which a limited number of metastatic tumors progress to more favorable outcomes. Here, we report the effective delivery of an oligometastatic microRNA (miR-655-3p) to colorectal liver metastases using nanoscale coordination polymers (NCPs). The NCPs demonstrated a targeted and prolonged distribution of microRNAs to metastatic liver tumors...
April 27, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28456380/a-basic-apoe-based-peptide-mediator-to-deliver-proteins-across-the-blood-brain-barrier-long-term-efficacy-toxicity-and-mechanism
#16
Yu Meng, Jennifer A Wiseman, Yuliya Nemtsova, Dirk F Moore, Jenieve Guevarra, Kenneth Reuhl, William A Banks, Richard Daneman, David E Sleat, Peter Lobel
We have investigated delivery of protein therapeutics from the bloodstream into the brain using a mouse model of late-infantile neuronal ceroid lipofuscinosis (LINCL), a lysosomal disease due to deficiencies in tripeptidyl peptidase 1 (TPP1). Supraphysiological levels of TPP1 are delivered to the mouse brain by acute intravenous injection when co-administered with K16ApoE, a peptide that in trans mediates passage across the blood-brain barrier (BBB). Chronic treatment of LINCL mice with TPP1 and K16ApoE extended the lifespan from 126 to >294 days, diminished pathology, and slowed locomotor dysfunction...
April 26, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28454789/cxcr5-overexpressing-mesenchymal-stromal-cells-exhibit-enhanced-homing-and-can-decrease-contact-hypersensitivity
#17
Xiaoran Zhang, Weijun Huang, Xiaoyong Chen, Yufan Lian, Jiancheng Wang, Chuang Cai, Li Huang, Tao Wang, Jie Ren, Andy Peng Xiang
Mesenchymal stromal cells (MSCs) can modulate inflammation and contribute to tissue regeneration and, thus, have emerged as a promising option for cell-based therapy. However, the ability of MSCs to migrate to injured tissues still needs to be improved. In this study, we investigated whether genetically engineered MSCs could exhibit increased migratory properties and improved therapeutic efficacy. Using a mouse model of contact hypersensitivity (CHS), chemokine gene expression screening revealed that CXCL13 changed most significantly in injured tissue...
April 26, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28462820/short-dna-hairpins-compromise-recombinant-adeno-associated-virus-genome-homogeneity
#18
Jun Xie, Qin Mao, Phillip W L Tai, Ran He, Jianzhong Ai, Qin Su, Ye Zhu, Hong Ma, Jia Li, Shoufang Gong, Dan Wang, Zhen Gao, Mengxin Li, Li Zhong, Heather Zhou, Guangping Gao
Short hairpin (sh)RNAs delivered by recombinant adeno-associated viruses (rAAVs) are valuable tools to study gene function in vivo and a promising gene therapy platform. Our data show that incorporation of shRNA transgenes into rAAV constructs reduces vector yield and produces a population of truncated and defective genomes. We demonstrate that sequences with hairpins or hairpin-like structures drive the generation of truncated AAV genomes through a polymerase redirection mechanism during viral genome replication...
April 24, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28462819/human-esc-ipsc-derived-hepatocyte-like-cells-achieve-zone-specific-hepatic-properties-by-modulation-of-wnt-signaling
#19
Seiji Mitani, Kazuo Takayama, Yasuhito Nagamoto, Kazuo Imagawa, Fuminori Sakurai, Masashi Tachibana, Ryo Sumazaki, Hiroyuki Mizuguchi
The function of hepatocytes largely depends on their position in the liver lobule. Although the method of differentiating hepatocytes from human pluripotent stem cells has been largely improved over the past decade, there remains no technique for generating hepatocyte-like cells (HLCs) with zone-specific hepatic properties. In this study, we searched for the factors that promote acquisition of zone-specific properties of HLCs. Here, we identified that WNT7B and WNT8B secreted from hepatocytes and cholangiocytes play important roles in achieving perivenous zone-specific characteristics, such as the enhancement of glutamine secretion, citric acid cycle, cytochrome P450 (CYP) 1A2 metabolism, and CYP1A2 induction capacities...
April 24, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28462816/in-utero-transfer-of-adeno-associated-viral-vectors-produces-long-term-factor-ix-levels-in-a-cynomolgus-macaque-model
#20
Citra N Z Mattar, Irene Gil-Farina, Cecilia Rosales, Nuryanti Johana, Yvonne Yi Wan Tan, Jenny McIntosh, Christine Kaeppel, Simon N Waddington, Arijit Biswas, Mahesh Choolani, Manfred Schmidt, Amit C Nathwani, Jerry K Y Chan
The safe correction of an inherited bleeding disorder in utero prior to the onset of organ damage is highly desirable. Here, we report long-term transgene expression over more than 6 years without toxicity following a single intrauterine gene transfer (IUGT) at 0.9G using recombinant adeno-associated vector (AAV)-human factor IX (hFIX) in the non-human primate model we have previously described. Four of six treated animals monitored for around 74 months expressed hFIX at therapeutic levels (3.9%-120.0%). Long-term expression was 6-fold higher in males and with AAV8 compared to AAV5, mediated almost completely at this stage by random genome-wide hepatic proviral integrations, with no evidence of hotspots...
April 24, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
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