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Human Gene Therapy

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https://www.readbyqxmd.com/read/28181816/induction-of-oxidants-distinguishes-susceptibility-of-prostate-carcinoma-cell-lines-to-p53-gene-transfer-mediated-by-an-improved-adenoviral-vector
#1
Rodrigo E Tamura, Aline Hunger, Denise Fernandes, Francisco Laurindo, Eugenia Costanzi-Strauss, Bryan E Strauss
Previously, we developed an adenoviral vector, Ad-PG, where transgene expression is regulated by a p53-responsive promoter. When used to transfer the p53 cDNA, a positive feedback mechanism is established. Here we perform a critical comparison between Ad-PGp53 and AdRGD-PGp53, where the RGD motif was incorporated in the adenoviral fiber protein. AdRGD-PGp53 provided superior transgene expression levels and resulted in the killing of prostate carcinoma cell lines DU145 and PC3. In vitro, this effect was associated with increased production of cytoplasmic and mitochondrial oxidants, DNA damage as revealed by detection of phosphorylated H2AX as well as cell death consistent with apoptosis...
February 9, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28142259/ace2-inhibits-angiotensin-ii-induced-abdominal-aortic-aneurysm-in-mice
#2
QingQing Hao, XueFei Dong, Xu Chen, Feng Yan, Xiaoyu Wang, Haishui Shi, Bo Dong
Recent study have demonstrated that ACE2 plays an important role in the pathogenesis of abdominal Aortic Aneurysm (AAA). But, little study was reported about the direct effect of ACE2 overexpression on the aneurysm. In this study, we hypothesize that overexpression of ACE2 may prevent the pathogenesis of aneurysm by decreasing RAS activation. Thirty-nine Mice were assigned to 3 groups randomly (n=13 in each group), ACE2 group, Ad.EGFP group and Control group. After 8-week treatment, abdominal aortas with AAA were obtained for HE staining, VVG, immunohistochemistry and Western blotting...
January 31, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28132521/direct-intracranial-injection-of-aavrh8-encoding-monkey-%C3%AE-n-acetylhexosaminidase-causes-neurotoxicity-in-primate-brain
#3
Diane Golebiowski, Imramsjah Martijn J van der Bom, Churl-Su Kwon, Andrew D Miller, Keiko Petrosky, Allison M Bradbury, Stacy Maitland, Anna Luisa Kühn, Nina Bishop, Elizabeth Curran, Nilsa Silva, Dwijit GuhaSarkar, Susan V Westmoreland, Douglas R Martin, Matthew J Gounis, Wael F Asaad, Miguel Sena-Esteves
GM2 gangliosidoses, including Tay-Sachs disease (TSD) and Sandhoff disease (SD), are lysosomal storage disorders caused by deficiencies in β-N-acetylhexosaminidase (Hex). Patients are afflicted primarily with progressive central nervous system dysfunction (CNS). Studies in mice, cats, and sheep have indicated safety and widespread distribution of Hex in the CNS after intracranial vector infusion of AAVrh8 vectors encoding species-specific Hex α- or β-subunits at a 1:1 ratio. Here we conducted a safety study in cynomolgus macaques (cm) modeling our previous animal studies with bilateral infusion in the thalamus as well as in left lateral ventricle of AAVrh8 vectors encoding cm Hex α- and β-subunits...
January 28, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28132518/stem-cell-treatment-in-crohn-s-disease
#4
Xiao-Mei Zhang, Yu-Jing Zhang, Wei Wang, Yu-Quan Wei, Hongxin Deng
Crohn's disease which mainly affects the gastrointestinal tract and impairs patient's quality of life, is a refractory inflammatory disease with clinical manifestations of abdominal pain, fever, bowel obstruction and diarrhoea with blood or mucus. Besides the common complication of intestinal obstruction, the formation of fistulas should also be concerned about and anorectal fistula is the most typical. The disease is difficult to radical cure and easy to relapse, which urges people to find other effective treatment in addition to surgery...
January 28, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28125921/systemic-and-persistent-muscle-gene-expression-in-rhesus-monkeys-with-a-liver-de-targeted-adeno-associated-virus-aav-vector
#5
Alice F Tarantal, Charles C Lee, Michele L Martinez, Asokan Aravind, R Jude Samulski
The liver is a major off-target organ in gene therapy approaches for cardiac and musculoskeletal disorders. Intravenous administration of most of the naturally occurring adeno-associated virus (AAV) strains invariably results in vector genome sequestration within the liver. In the current study, we compared the muscle tropism and transduction efficiency of a liver de-targeted AAV variant to AAV9 following systemic administration in newborn rhesus monkeys. In vivo bioluminescence imaging was performed to monitor transgene expression (firefly luciferase) post-administration...
January 26, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28114818/functional-screening-identifies-human-mirnas-that-modulate-adenovirus-propagation-in-prostate-cancer-cells
#6
Jasmina Hodzic, Daoud Sie, Annaleen Vermeulen, Victor W van Beusechem
Oncolytic adenoviruses represent a novel class of anticancer agents. Their efficacy in killing cancer cells is variable, suggesting that there is room for improvement. Host miRNAs have been shown to play important roles in susceptibility of cells to replication of different viruses. Here, we investigate if adenovirus replication in human prostate cancer cells is influenced by host cell miRNA expression. To this end, we analyzed human miRNA expression in response to adenovirus infection and performed functional screens for lytic adenovirus replication using synthetic miRNA mimic and inhibitor libraries...
January 23, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28073291/future-of-raav-gene-therapy-platform-for-rnai-gene-editing-and-beyond
#7
Paul Valdmanis, Mark A Kay
The use of recombinant adeno-associated viruses (rAAVs) ushered in a new millennium of gene transfer for therapeutic treatment of a number of conditions including congenital blindness, hemophilia, and spinal muscular atrophy (SMA). rAAV vectors have remarkable staying power from a therapeutic standpoint withstanding several ebbs and flows. As new technologies such as clustered regularly interspaced short palindromic repeat (CRISPR) genome editing emerge, it is now the delivery tool - the AAV vector - that is the stalwart...
January 10, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28056565/characterization-of-aav-mediated-human-factor-viii-gene-therapy-in-hemophilia-a-mice
#8
Jenny A Greig, Qiang Wang, Amanda L Reicherter, Shu-Jen Chen, Alexandra L Hanlon, Christopher H Tipper, K Reed Clark, Samuel Wadsworth, Lili Wang, James M Wilson
Adeno-associated viral (AAV) vectors are promising vehicles for hemophilia gene therapy, with favorable clinical trial data seen in the treatment of hemophilia B. In an effort to optimize the expression of human coagulation factor VIII (hFVIII) for the treatment of hemophilia A, we performed an extensive study with numerous combinations of liver-specific promoter and enhancer elements with a codon-optimized hFVIII transgene. After generating 42 variants of three reduced-size promoters and three small enhancers, transgene cassettes were packaged within a single AAV capsid, AAVrh10, to eliminate performance differences due to the capsid type...
January 5, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28052693/safety-and-efficacy-of-ex-vivo-donor-lung-adenoviral-il-10-gene-therapy-in-a-large-animal-lung-transplant-survival-model
#9
Tiago Noguchi Machuca, Marcelo Cypel, Riccardo Bonato, Jonathan C Yeung, Yi-Min Chun, Stephen Juvet, Guan Zehong, David M Hwang, Manyin Chen, Tomohito Saito, Constantine Harmantas, Beverly Davidson, Thomas K Waddell, Mingyao Liu, Shaf Keshavjee
OBJECTIVE: Ex vivo normothermic lung perfusion (EVLP) is a novel platform and method developed to facilitate functional assessment and implementation of advanced therapies for donor lungs prior to transplantation. We aimed to determine the safety and immunological and functional benefits of ex vivo adenoviral human IL-10 (AdhIL-10) gene delivery to prevent the development of primary graft dysfunction in a large animal survival model. METHODS: Pig donor lungs were retrieved, preserved for 6 hours at 4oC and then randomly assigned to 4 groups: 1) AdhIL-10 Gene Therapy: 12 hours EVLP + AdhIL-10 intra-bronchial delivery; 2) EVLP-control: 12 hours EVLP; 3) Vector-control: 12 hours EVLP + adenoviral vector intra-bronchial delivery; and 4) Prolonged hypothermic preservation: Additional 12 hours of cold ischemia...
January 4, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28042949/recombinant-parvoviruses-armed-to-deliver-cxcl4l1-and-cxcl10-are-impaired-in-their-antiangiogenic-and-antitumoral-effects-in-a-kaposi-sarcoma-tumor-model-due-to-the-chemokines-interference-with-the-virus-cycle
#10
Christiane Dinsart, Kalliopi Pervolaraki, Alexandra Stroh-Dege, Muriel Lavie, Isabelle Ronsse, Jean Rommelaere, Jo Van Damme, Katrien Van Raemdonck, Sofie Struyf
Application of oncolytic viruses is a valuable option to broaden the armament of anti-cancer therapies as these combine specific cytotoxic effects and immune-stimulating properties. The self-replicating H-1 parvovirus (H-1PV) is a prototypical oncolytic virus that besides targeting tumor cells also infects endothelial cells, thus combining oncolytic and angiostatic traits. To increase its therapeutic value, H-1PV can be armed with cytokines or chemokines to enhance the immunological response. Some chemokines, more specifically the CXCR3 ligands CXCL4L1 and CXCL10 combine immune-stimulating properties with angiostatic activity...
January 2, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28042948/bacmam-delivery-of-a-protective-gene-to-reduce-renal-ischemia-reperfusion-injury
#11
Elisabetta Hitchman, Richard Brian Hitchman, Linda A King
Ischaemia-reperfusion (I/R) injury remains the primary contributor to delayed graft function in kidney transplantation. The beneficial application of manganese superoxide dismutase (sod), delivered by a BacMam vector, against renal I/R injury has not been evaluated previously. Therefore, in this study we overexpressed sod-2 in proximal tubular epithelial (HK-2) cells and porcine kidney organs during simulated renal I/R injury. Incubation of HK-2 cells with antimycin A and 2-deoxyglucose resulted in a significant decrease in intracellular ATP levels; following reperfusion, ATP levels significantly increased overtime in cells overexpressing sod-2...
January 2, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28042947/efficient-transduction-of-human-and-rhesus-macaque-primary-t-cells-by-a-modified-human-immunodeficiency-virus-type-1-hiv-1-based-lentiviral-vector
#12
Huan He, Jing Xue, Weiming Wang, Lihong Liu, Chaobaihui Ye, Zhe Cong, Jason Kimata, Chuan Qin, Paul Zhou
HIV-1-based lentiviral vectors efficiently transduce genes to human, but not rhesus, primary T cells and hematopoietic stem cells (HSCs). The poor transduction of HIV-1 vectors to rhesus cells is mainly due to species-specific restriction factors such as rhesus TRIM5α. Previously, several strategies to modify HIV-1 vectors were developed to overcome rhesus TRIM5α restriction. While the modified HIV-1 vectors efficiently transduce rhesus HSCs, they remain suboptimal for rhesus primary T cells. Recently, HIV-1 variants that encode combinations of LNEIE mutations in capsid (CA) protein and SIVmac239 Vif were found to replicate efficiently in rhesus primary T cells...
January 2, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28042945/minicircle-orip-mir-31-as-a-novel-ebna1-specific-mirna-therapy-approach-for-nasopharyngeal-carcinoma
#13
Jiang-Xue Wu, Xin Tan, Jiaxin Lin, Luping Yuan, Jiemin Chen, Lin Qiu, Wen-Lin Huang
MicroRNAs (miRNAs) are important post-transcriptional regulators that control cancer development and progression. However, the application of miRNA therapy in cancer has been hampered by a lack of an efficient and targeted delivery system. In our previous studies, an oriP promoter-based minicircle system successfully mediated targeted foreign gene expression in EBNA1-positive nasopharyngeal carcinoma (NPC). However, it remains to be evaluated whether this system can be applied for tumor miRNA therapy. miR-31-5p, a tumor suppressive miRNA involved in the tumorigenesis of EBV-positive NPC, was selected as the therapeutic miRNA to be transferred...
January 2, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28042944/comparison-of-serum-raav-serotype-specific-antibodies-in-patients-with-duchenne-muscular-dystrophy-becker-muscular-dystrophy-inclusion-body-myositis-or-gne-myopathy
#14
Deborah Zygmunt, Kelly E Crowe, Kevin Flanigan, Paul T Martin
Recombinant Adeno-associated virus (rAAV) is a commonly used gene therapy vector for the delivery of therapeutic transgenes in a variety of human diseases, but pre-existing serum antibodies to viral capsid proteins can greatly inhibit rAAV transduction of tissues. We have assayed serum from patients with Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (DMD), Inclusion Body Myositis (IBM), and GNE myopathy (GNE). These were compared to serum from otherwise normal human subjects to determine the extent of pre-existing serum antibodies to rAAVrh74, rAAV1, rAAV2, rAAV6, rAAV8 and rAAV9...
January 2, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28042943/the-impact-of-aav-capsid-specific-t-cell-responses-on-design-and-outcome-of-clinical-gene-transfer-trials-with-recombinant-aav-vectors-an-evolving-controversy
#15
Hildegund Cj Ertl, Katherine A High
Recombinant adenovirus-associated (rAAV) vectors due to their ease of construction, wide tissue tropism and lack of pathogenicity remain at the forefront for long-term gene replacement therapy. In spite of very encouraging pre-clinical results, clinical trials were initially unsuccessful; expression of the rAAV vector-delivered therapeutic protein was transient. Loss of expression was linked to an expansion of AAV capsid-specific T cell responses, leading to the hypothesis that rAAV vectors recall pre-existing memory T cells that had been induced by natural infections with AAV together with a helper virus...
January 2, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/27967241/acute-myeloid-leukemia-targeting-by-chimeric-antigen-receptor-t-cells-bridging-the-gap-from-preclinical-modeling-to-human-studies
#16
Maria Caterina Rotiroti, Silvia Arcangeli, Monica Casucci, Vincenzo Perriello, Attilio Bondanza, Andrea Biondi, Sarah Tettamanti, Ettore Biagi
Acute myeloid leukemia (AML) still represents an unmet clinical need for adult and pediatric high-risk patients, thus demanding advanced and personalized therapies. In this regard, different targeted immunotherapeutic approaches are available, ranging from naked monoclonal antibodies (mAb) to conjugated and multifunctional mAbs (i.e., BiTEs and DARTs). Recently, researchers have focused their attention on novel techniques of genetic manipulation specifically to redirect cytotoxic T cells endowed with chimeric antigen receptors (CARs) toward selected tumor associated antigens...
December 1, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/28186849/families-and-researchers-collaborate-in-advancing-therapy-the-role-of-ntsad-together-with-parents-in-driving-toward-treatments
#17
Susan R Kahn
No abstract text is available yet for this article.
February 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28186848/empty-adeno-associated-virus-capsids-contaminant-or-natural-decoy
#18
Terence R Flotte
No abstract text is available yet for this article.
February 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/27806641/empty-capsids-and-macrophage-inhibition-depletion-increase-raav-transgene-expression-in-joints-of-both-healthy-and-arthritic-mice
#19
Caroline J Aalbers, Niels Broekstra, Mariska van Geldorp, Emiel Kramer, Sofia Ramiro, Paul P Tak, Margriet J Vervoordeldonk, Jonathan D Finn
Gene therapy has potential to treat rheumatic diseases; however, the presence of macrophages in the joint might hamper adeno-associated viral vector-mediated gene delivery. Here we demonstrate that in arthritic, but also in healthy, mice administration of agents that influence macrophage activity/number and/or addition of empty decoy capsids substantially improve the efficacy of recombinant adeno-associated viral vector 5 transgene expression in the joint. Pretreatment with triamcinolone or clodronate liposomes improved luciferase expression over a period of 4 weeks...
February 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/27802782/treatment-of-human-b-cell-lymphomas-using-minicircle-dna-vector-expressing-anti-cd3-cd20-in-a-mouse-model
#20
Xiaojuan Pang, Fei Ma, Peifa Zhang, Yujian Zhong, Jing Zhang, Tianyan Wang, Gang Zheng, Xiaohu Hou, Jing Zhao, Chengyi He, Zhi-Ying Chen
Bispecific antibodies (BsAbs), capable of directing T cells to kill specific cancer cells by transiently binding the two cell types, have emerged as one class of promising cancer immunotherapies. However, their wide clinical application might be hampered by two deficiencies: high cost and inconvenience in drug administration. This study presents concept-proving data that these problems could be bypassed by using an enhanced nonviral DNA vector minicircle (MC) to produce BsAb in vivo. It was found that the anti-CD3/CD20 produced from the minicircle (MC...
February 2017: Human Gene Therapy
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