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

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https://www.readbyqxmd.com/read/28800954/a-tim-3-oligonucleotide-aptamer-enhances-t-cell-functions-and-potentiates-tumor-immunity-in-mice
#1
Tal Gefen, Iris Castro, Darija Muharemagic, Yvonne Puplampu-Dove, Shradha Patel, Eli Gilboa
T cell immunoglobulin-3 (TIM-3) is a negative regulator of interferon-γ (IFN-γ) secreting CD4(+) T cells and CD8(+) T cytotoxic cells. Recent studies have highlighted the role of TIM-3 as an important mediator of CD8(+) T cell exhaustion in the setting of chronic viral infections and cancer. In murine tumor models, antibody blockade of TIM-3 with anti-TIM-3 antibodies as monotherapy has no or minimal antitumor activity, suggesting that TIM-3 signaling exerts an accessory or amplifying effect in keeping immune responses in check...
August 8, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28784560/adipose-stem-cell-therapy-mitigates-chronic-pancreatitis-via-differentiation-into-acinar-like-cells-in-mice
#2
Zhen Sun, Wenyu Gou, Do-Sung Kim, Xiao Dong, Charlie Strange, Yu Tan, David B Adams, Hongjun Wang
The objective of this study was to assess the capacity of adipose-derived mesenchymal stem cells (ASCs) to mitigate disease progression in an experimental chronic pancreatitis mouse model. Chronic pancreatitis (CP) was induced in C57BL/6 mice by repeated ethanol and cerulein injection, and mice were then infused with 4 × 10(5) or 1 × 10(6) GFP(+) ASCs. Pancreas morphology, fibrosis, inflammation, and presence of GFP(+) ASCs in pancreases were assessed 2 weeks after treatment. We found that ASC infusion attenuated pancreatic damage, preserved pancreas morphology, and reduced pancreatic fibrosis and cell death...
August 4, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28807568/function-of-novel-anti-cd19-chimeric-antigen-receptors-with-human-variable-regions-is-affected-by-hinge-and-transmembrane-domains
#3
Leah Alabanza, Melissa Pegues, Claudia Geldres, Victoria Shi, Jed J W Wiltzius, Stuart A Sievers, Shicheng Yang, James N Kochenderfer
Anti-CD19 chimeric antigen receptor (CAR) T cells have caused remissions of B cell malignancies, but problems including cytokine-mediated toxicity and short persistence of CAR T cells in vivo might limit the effectiveness of anti-CD19 CAR T cells. Anti-CD19 CARs that have been tested clinically had single-chain variable fragments (scFvs) derived from murine antibodies. We have designed and constructed novel anti-CD19 CARs containing a scFv with fully human variable regions. T cells expressing these CARs specifically recognized CD19(+) target cells and carried out functions including degranulation, cytokine release, and proliferation...
July 27, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28750738/dengue-virus-evades-aav-mediated-neutralizing-antibody-prophylaxis-in-rhesus-monkeys
#4
Diogo M Magnani, Michael J Ricciardi, Varian K Bailey, Martin J Gutman, Núria Pedreño-Lopez, Cassia G T Silveira, Helen S Maxwell, Aline Domingues, Lucas Gonzalez-Nieto, Qin Su, Ruchi M Newman, Melissa Pack, Mauricio A Martins, José M Martinez-Navio, Sebastian P Fuchs, Eva G Rakasz, Todd M Allen, Stephen S Whitehead, Dennis R Burton, Guangping Gao, Ronald C Desrosiers, Esper G Kallas, David I Watkins
Development of vaccines against mosquito-borne Flaviviruses is complicated by the occurrence of antibody-dependent enhancement (ADE), which can increase disease severity. Long-term delivery of neutralizing antibodies (nAbs) has the potential to effectively block infection and represents an alternative to vaccination. The risk of ADE may be avoided by using prophylactic nAbs harboring amino acid mutations L234A and L235A (LALA) in the immunoglobulin G (IgG) constant region. Here, we used recombinant adeno-associated viruses (rAAVs) to deliver the anti-dengue virus 3 (DENV3) nAb P3D05...
July 24, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28750737/low-dose-nitric-oxide-as-targeted-anti-biofilm-adjunctive-therapy-to-treat-chronic-pseudomonas-aeruginosa-infection-in-cystic-fibrosis
#5
Robert P Howlin, Katrina Cathie, Luanne Hall-Stoodley, Victoria Cornelius, Caroline Duignan, Raymond N Allan, Bernadette O Fernandez, Nicolas Barraud, Ken D Bruce, Johanna Jefferies, Michael Kelso, Staffan Kjelleberg, Scott A Rice, Geraint B Rogers, Sandra Pink, Caroline Smith, Priya S Sukhtankar, Rami Salib, Julian Legg, Mary Carroll, Thomas Daniels, Martin Feelisch, Paul Stoodley, Stuart C Clarke, Gary Connett, Saul N Faust, Jeremy S Webb
Despite aggressive antibiotic therapy, bronchopulmonary colonization by Pseudomonas aeruginosa causes persistent morbidity and mortality in cystic fibrosis (CF). Chronic P. aeruginosa infection in the CF lung is associated with structured, antibiotic-tolerant bacterial aggregates known as biofilms. We have demonstrated the effects of non-bactericidal, low-dose nitric oxide (NO), a signaling molecule that induces biofilm dispersal, as a novel adjunctive therapy for P. aeruginosa biofilm infection in CF in an ex vivo model and a proof-of-concept double-blind clinical trial...
July 24, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28750736/obestatin-increases-the-regenerative-capacity-of-human-myoblasts-transplanted-intramuscularly-in-an-immunodeficient-mouse-model
#6
Icia Santos-Zas, Elisa Negroni, Kamel Mamchaoui, Carlos S Mosteiro, Rosalia Gallego, Gillian S Butler-Browne, Yolanda Pazos, Vincent Mouly, Jesus P Camiña
Although cell-based therapy is considered a promising method aiming at treating different muscular disorders, little clinical benefit has been reported. One of major hurdles limiting the efficiency of myoblast transfer therapy is the poor survival of the transplanted cells. Any intervention upon the donor cells focused on enhancing in vivo survival, proliferation, and expansion is essential to improve the effectiveness of such therapies in regenerative medicine. In the present work, we investigated the potential role of obestatin, an autocrine peptide factor regulating skeletal muscle growth and repair, to improve the outcome of myoblast-based therapy by xenotransplanting primary human myoblasts into immunodeficient mice...
July 24, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28807567/a-new-promoter-allows-optogenetic-vision-restoration-with-enhanced-sensitivity-in-macaque-retina
#7
Antoine Chaffiol, Romain Caplette, Céline Jaillard, Elena Brazhnikova, Mélissa Desrosiers, Elisabeth Dubus, Laëtitia Duhamel, Emilie Macé, Olivier Marre, Patrick Benoit, Philippe Hantraye, Alexis-Pierre Bemelmans, Ernst Bamberg, Jens Duebel, José-Alain Sahel, Serge Picaud, Deniz Dalkara
The majority of inherited retinal degenerations converge on the phenotype of photoreceptor cell death. Second- and third-order neurons are spared in these diseases, making it possible to restore retinal light responses using optogenetics. Viral expression of channelrhodopsin in the third-order neurons under ubiquitous promoters was previously shown to restore visual function, albeit at light intensities above illumination safety thresholds. Here, we report (to our knowledge, for the first time) activation of macaque retinas, up to 6 months post-injection, using channelrhodopsin-Ca(2+)-permeable channelrhodopsin (CatCh) at safe light intensities...
July 20, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28803863/epidermal-e-cadherin-dependent-%C3%AE-catenin-pathway-is-phytochemical-inducible-and-accelerates-anagen-hair-cycling
#8
Noha S Ahmed, Subhadip Ghatak, Mohamed S El Masry, Surya C Gnyawali, Sashwati Roy, Mohamed Amer, Helen Everts, Chandan K Sen, Savita Khanna
Unlike the epidermis, which regenerates continually, hair follicles anchored in the subcutis periodically regenerate by spontaneous repetitive cycles of growth (anagen), degeneration (catagen), and rest (telogen). The loss of hair follicles in response to injuries or pathologies such as alopecia endangers certain inherent functions of the skin. Thus, it is of interest to understand mechanisms underlying follicular regeneration in adults. In this work, a phytochemical rich in the natural vitamin E tocotrienol (TRF) served as a productive tool to unveil a novel epidermal pathway of hair follicular regeneration...
July 20, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28803862/recombinant-lcmv-vectors-induce-protective-immunity-following-homologous-and-heterologous-vaccinations
#9
Jessica Wingerath, Dmitrij Ostroumov, Norman Woller, Michael P Manns, Daniel D Pinschewer, Klaus Orlinger, Ursula Berka, Florian Kühnel, Thomas C Wirth
Successful vaccination against cancer and infectious diseases relies on the induction of adaptive immune responses that induce high-titer antibodies or potent cytoxic T cell responses. In contrast to humoral vaccines, the amplification of cellular immune responses is often hampered by anti-vector immunity that either pre-exists or develops after repeated homologous vaccination. Replication-defective lymphocytic choriomeningitis virus (LCMV) vectors represent a novel generation of vaccination vectors that induce potent immune responses while escaping recognition by neutralizing antibodies...
July 20, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28784559/adnectin-based-design-of-chimeric-antigen-receptor-for-t-cell-engineering
#10
Xiaolu Han, Gunce E Cinay, Yifan Zhao, Yunfei Guo, Xiaoyang Zhang, Pin Wang
Although chimeric antigen receptor (CAR)-engineered T cell therapy has achieved encouraging clinical trial results for treating hematological cancers, further optimization can likely expand this therapeutic success to more patients and other cancer types. Most CAR constructs used in clinical trials incorporate single chain variable fragment (scFv) as the extracellular antigen recognition domain. The immunogenicity of nonhuman scFv could cause host rejection against CAR T cells and compromise their persistence and efficacy...
July 20, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28720468/production-of-a-chikungunya-vaccine-using-a-cho-cell-and-attenuated-viral-based-platform-technology
#11
Preethi Eldi, Tamara H Cooper, Liang Liu, Natalie A Prow, Kerrilyn R Diener, Paul M Howley, Andreas Suhrbier, John D Hayball
Vaccinia-based systems have been extensively explored for the development of recombinant vaccines. Herein we describe an innovative vaccinia virus (VACV)-derived vaccine platform technology termed Sementis Copenhagen Vector (SCV), which was rendered multiplication-defective by targeted deletion of the essential viral assembly gene D13L. A SCV cell substrate line was developed for SCV vaccine production by engineering CHO cells to express D13 and the VACV host-range factor CP77, because CHO cells are routinely used for manufacture of biologics...
July 15, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28720467/intradermal-immunization-with-raav1-vector-induces-robust-memory-cd8-t-cell-responses-independently-of-transgene-expression-in-dcs
#12
Alexandre Ghenassia, David-Alexandre Gross, Stéphanie Lorain, Fabiola Tros, Dominique Urbain, Sofia Benkhelifa-Ziyyat, Alain Charbit, Jean Davoust, Pascal Chappert
Recombinant adeno-associated viral (rAAV) vectors exhibit interesting properties as vaccine carriers for their ability to induce long-lasting antibody responses. However, rAAV-based vaccines have been suggested to trigger functionally impaired long-term memory CD8(+) T cell responses, in part due to poor dendritic cell (DC) transduction. Such results, albeit limited to intramuscular immunization, undermined the use of rAAV as vaccine vehicles against intracellular pathogens. We report here that intradermal immunization with a model rAAV2/1-based vaccine drives the development of bona fide long-term memory CD8(+) T cell responses...
July 15, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28716576/tlr9-mediated-conditioning-of-liver-environment-is-essential-for-successful-intrahepatic-immunotherapy-and-effective-memory-recall
#13
Marcin Cebula, Mathias Riehn, Upneet Hillebrand, Ramona F Kratzer, Florian Kreppel, Georgia Koutsoumpli, Toos Daemen, Hansjörg Hauser, Dagmar Wirth
Immune defense against hepatotropic viruses such as hepatitis B (HBV) and hepatitis C (HCV) poses a major challenge for therapeutic approaches. Intrahepatic cytotoxic CD8 T cells that are crucial for an immune response against these viruses often become exhausted resulting in chronic infection. We elucidated the T cell response upon therapeutic vaccination in inducible transgenic mouse models in which variable percentages of antigen-expressing hepatocytes can be adjusted, providing mosaic antigen distribution and reflecting the varying viral antigen loads observed in patients...
July 14, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28803861/long-duration-complete-remissions-of-diffuse-large-b-cell-lymphoma-after-anti-cd19-chimeric-antigen-receptor-t%C3%A2-cell-therapy
#14
James N Kochenderfer, Robert P T Somerville, Tangying Lu, James C Yang, Richard M Sherry, Steven A Feldman, Lori McIntyre, Adrian Bot, John Rossi, Norris Lam, Steven A Rosenberg
T cells expressing anti-CD19 chimeric antigen receptors (CARs) can induce complete remissions (CRs) of diffuse large B cell lymphoma (DLBCL). The long-term durability of these remissions is unknown. We administered anti-CD19 CAR T cells preceded by cyclophosphamide and fludarabine conditioning chemotherapy to patients with relapsed DLBCL. Five of the seven evaluable patients obtained CRs. Four of the five CRs had long-term durability with durations of remission of 56, 51, 44, and 38 months; to date, none of these four cases of lymphomas have relapsed...
July 13, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28800953/col7a1-editing-via-crispr-cas9-in-recessive-dystrophic-epidermolysis-bullosa
#15
Stefan Hainzl, Patricia Peking, Thomas Kocher, Eva M Murauer, Fernando Larcher, Marcela Del Rio, Blanca Duarte, Markus Steiner, Alfred Klausegger, Johann W Bauer, Julia Reichelt, Ulrich Koller
Designer nucleases allow specific and precise genomic modifications and represent versatile molecular tools for the correction of disease-associated mutations. In this study, we have exploited an ex vivo CRISPR/Cas9-mediated homology-directed repair approach for the correction of a frequent inherited mutation in exon 80 of COL7A1, which impairs type VII collagen expression, causing the severe blistering skin disease recessive dystrophic epidermolysis bullosa. Upon CRISPR/Cas9 treatment of patient-derived keratinocytes, using either the wild-type Cas9 or D10A nickase, corrected single-cell clones expressed and secreted similar levels of type VII collagen as control keratinocytes...
July 13, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28712546/a-novel-target-antigen-for-the-treatment-of-acute-myeloid-leukemia-by-car-t-cells
#16
Paul A Beavis, Kevin Sek, Phillip K Darcy
No abstract text is available yet for this article.
July 13, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28705346/efficient-generation-of-dopamine-neurons-by-synthetic-transcription-factor-mrnas
#17
Sang-Mi Kim, Mi-Sun Lim, Eun-Hye Lee, Sung Jun Jung, Hee Yong Chung, Chun-Hyung Kim, Chang-Hwan Park
Generation of functional dopamine (DA) neurons is an essential step for the development of effective cell therapy for Parkinson's disease (PD). The generation of DA neurons can be accomplished by overexpression of DA-inducible genes using virus- or DNA-based gene delivery methods. However, these gene delivery methods often cause chromosomal anomalies. In contrast, mRNA-based gene delivery avoids this problem and therefore is considered safe to use in the development of cell-based therapy. Thus, we used mRNA-based gene delivery method to generate safe DA neurons...
July 11, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28780274/microfluidic-transduction-harnesses-mass-transport-principles-to-enhance-gene-transfer-efficiency
#18
Reginald Tran, David R Myers, Gabriela Denning, Jordan E Shields, Allison M Lytle, Hommood Alrowais, Yongzhi Qiu, Yumiko Sakurai, William C Li, Oliver Brand, Joseph M Le Doux, H Trent Spencer, Christopher B Doering, Wilbur A Lam
Ex vivo gene therapy using lentiviral vectors (LVs) is a proven approach to treat and potentially cure many hematologic disorders and malignancies but remains stymied by cumbersome, cost-prohibitive, and scale-limited production processes that cannot meet the demands of current clinical protocols for widespread clinical utilization. However, limitations in LV manufacture coupled with inefficient transduction protocols requiring significant excess amounts of vector currently limit widespread implementation...
July 8, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28760668/rig-i-activation-protects-and-rescues-from-lethal-influenza-virus-infection-and-bacterial-superinfection
#19
Christoph Coch, Jan Phillip Stümpel, Vanessa Lilien-Waldau, Dirk Wohlleber, Beate M Kümmerer, Isabelle Bekeredjian-Ding, Georg Kochs, Natalio Garbi, Stephan Herberhold, Christine Schuberth-Wagner, Janos Ludwig, Winfried Barchet, Martin Schlee, Achim Hoerauf, Friedrich Bootz, Peter Staeheli, Gunther Hartmann, Evelyn Hartmann
Influenza A virus infection causes substantial morbidity and mortality in seasonal epidemic outbreaks, and more efficient treatments are urgently needed. Innate immune sensing of viral nucleic acids stimulates antiviral immunity, including cell-autonomous antiviral defense mechanisms that restrict viral replication. RNA oligonucleotide ligands that potently activate the cytoplasmic helicase retinoic-acid-inducible gene I (RIG-I) are promising candidates for the development of new antiviral therapies. Here, we demonstrate in an Mx1-expressing mouse model of influenza A virus infection that a single intravenous injection of low-dose RIG-I ligand 5'-triphosphate RNA (3pRNA) completely protected mice from a lethal challenge with influenza A virus for at least 7 days...
July 8, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28697888/regulated-expansion-and-survival-of-chimeric-antigen-receptor-modified-t-cells-using-small-molecule-dependent-inducible-myd88-cd40
#20
Aaron E Foster, Aruna Mahendravada, Nicholas P Shinners, Wei-Chun Chang, Jeannette Crisostomo, An Lu, Mariam Khalil, Eva Morschl, Joanne L Shaw, Sunandan Saha, MyLinh T Duong, Matthew R Collinson-Pautz, David L Torres, Tania Rodriguez, Tsvetelina Pentcheva-Hoang, J Henri Bayle, Kevin M Slawin, David M Spencer
Anti-tumor efficacy of T cells engineered to express chimeric antigen receptors (CARs) is dependent on their specificity, survival, and in vivo expansion following adoptive transfer. Toll-like receptor (TLR) and CD40 signaling in T cells can improve persistence and drive proliferation of antigen-specific CD4(+) and CD8(+) T cells following pathogen challenge or in graft-versus-host disease (GvHD) settings, suggesting that these costimulatory pathways may be co-opted to improve CAR-T cell persistence and function...
July 8, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
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