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Human Gene Therapy

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https://www.readbyqxmd.com/read/27903072/a-5-non-coding-exon-containing-engineered-intron-enhances-transgene-expression-from-recombinant-aav-vectors-in-vivo
#1
Jiamiao Lu, James A Williams, James Luke, Feijie Zhang, Kirk Chu, Mark A Kay
We previously developed a mini-intronic plasmid (MIP) expression system in which the essential bacterial elements for plasmid replication and selection are placed within an engineered intron contained within a universal 5'UTR non-coding exon. Like minicircle DNA plasmids (devoid of bacterial backbone sequences), MIP plasmids overcome transcriptional silencing of the transgene. However, in addition MIP plasmids increase transgene expression by 2 and often >10 times higher than minicircle vectors in vivo and in vitro...
November 30, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27897038/aav-gene-therapy-for-liver-disease
#2
Lisa M Kattenhorn, Christopher H Tipper, Lorelei Stoica, Deborah S Geraghty, Teresa L Wright, K Reed Clark, Samuel Wadsworth
The field of adeno-associated virus (AAV) gene therapy has progressed rapidly over the past decade, with the advent of novel capsid serotypes, organ-specific promoters and an increasing understanding of the immune response to AAV administration. Liver-directed therapy, in particular, has made remarkable strides with a number of clinical trials currently planned and on-going in hemophilia A and B, as well as other liver disorders. This review focuses on liver-directed AAV gene therapy, including historic context, current challenges, and future developments...
November 29, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27889981/chimeric-trojan-protein-insertion-in-lentiviral-membranes-makes-lentiviruses-susceptible-to-neutralisation-by-anti-tetanus-serum-antibodies
#3
Anita Le-Heron, Steve Patterson, Rafael J Yáñez-Muñoz, George Dickson
This study describes the initial testing of a novel strategy for neutralisation of lentiviruses using the fundamental biology of enveloped viruses' assembly and budding. In the field of gene therapy, viral vector surface proteins have been manipulated in order to redirect host cell specificity by alteration of pseudo-types. We tested whether known viral pseudo-typing proteins or surface proteins known to be recruited to the HIV envelope could be engineered to carry neutralising epitopes from another microorganism onto the lentiviral surface...
November 27, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27875064/correction-to-hum-gene-ther-2016-27-1-19-31
#4
(no author information available yet)
No abstract text is available yet for this article.
November 22, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27842439/stable-in-vivo-transgene-expression-in-endothelial-cells-with-helper-dependent-adenovirus-roles-of-promoter-and-interleukin-10
#5
Nagadhara Dronadula, Bradley Wacker, Reginald Van Der Kwast, Jingwan Zhang, David A Dichek
Our long-term goal is to prevent or reverse atherosclerosis by delivering gene therapy from stably transduced endothelial cells (EC). We previously reported that EC-directed gene therapy with a helper-dependent adenovirus (HDAd) expressing apolipoprotein A-I (apo A-I) retarded development of atherosclerosis in rabbit carotid arteries over a 1-month interval. However, a 70% decline in apo A-I expression during this time raised concerns about long-term efficacy of this approach. Here we report use of several approaches aimed either at preventing this decline or at increasing apo A-I expression from HDAd at all time points: codon optimization, deletion of 3´ untranslated sequences, substitution of a synthetic mammalian-based promoter (4XETE) for the CMV promoter, and co-transduction with an HDAd expressing interleukin-10...
November 14, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27832705/aav-infection-protection-from-cancer
#6
Arun Srivastava, Barrie Carter
In late 2015, Nault et al1, reported that of 193 patients with hepatocellular carcinoma (HCC), 11 (<6%) contained an integrated genome sequence of the wild type (wt) adeno-associated virus 2 (AAV2), and suggested that AAV2 is associated with oncogenic insertional mutagenesis in human HCC. Although this conclusion was questioned by us2 and others3, in more recent publications, Nault et al4-7, continue to insist that AAV2 is an oncogenic virus in initiating HCC. Interestingly, Park et al8 recently reported that following evaluation of a total of 289 unrelated patients with HCC, the presence of AAV2 DNA was detected in tumor tissues from only 2 patients (<1%), and concluded that AAV2-mediated HCC is very rare in Korean patients...
November 10, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27832700/systemic-correction-of-murine-glycogen-storage-disease-type-iv-by-an-aav-mediated-gene-therapy
#7
Haiqing Yi, Quan Zhang, Elizabeth D Brooks, Chunyu Yang, Beth L Thurberg, Priya S Kishnani, Baodong Sun
Deficiency of glycogen branching enzyme (GBE) causes glycogen storage disease type IV (GSD IV), which is characterized by the accumulation of a less branched, poorly soluble form of glycogen called polyglucosan (PG) in multiple tissues. We evaluate the efficacy of gene therapy with an adeno-associated viral (AAV) vector in a mouse model of adult form of GSD IV (<i>Gbe1<sup>ys/ys</sup></i>). An AAV serotype 9 (AAV9) vector containing a human GBE expression cassette (AAV-GBE) was intravenously injected into 14-day-old <i>Gbe1<sup>ys/ys</sup></i> mice at a dose of 5x10<sup>11</sup> vector genomes per mouse...
November 10, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27806643/manganese-superoxide-dismutase-gene-modified-mesenchymal-stem-cells-attenuates-acute-radiation-induced-lung-injury
#8
HaiXu Chen, Hang Xiang, BenYan Wu, XiaoMei Zhang, Ming Li, Juan Liu, Jun Li, ZhaoQi Ren, Bin Du, KunLun He, Qiang Zeng, Chao Yang
Radiation-induced lung injury (RILI) is a major clinical complication for radiotherapy in thoracic tumors. An immediate effect of lung irradiation is the generation of reactive oxygen (ROS) that can produce oxidative damage to DNA, lipids, and proteins resulting in lung cell injury or death. Currently, the medical management of RILI remains supportive. Therefore, there is an urgent need for the development of countermeasures. The present study was aimed to evaluate the protective effect of manganese superoxide dismutase (MnSOD) gene modified mesenchymal stem cells (MSCs) to facilitate the improved recovery of RILI...
November 2, 2016: 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
#9
Caroline Aalbers, Niels Broekstra, Mariska van Geldorp, Emiel Kramer, Sofia Ramiro, Paul P Tak, Margriet J Vervoordeldonk, Jonathan Finnn
Gene therapy has potential to treat rheumatic diseases, however the presence of macrophages in the joint might hamper AAV 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 rAAV5-transgene expression in the joint. Pre-treatment with triamcinolone or clodronate liposomes improved luciferase expression over a period of 4 weeks. Similar results were seen when empty decoy capsids were added to full genome containing capsids in a 5:1 ratio...
November 2, 2016: 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
#10
Xiaojuan Pang, Fei Ma, Peifa Zhang, Yujian Zhong, Jing Zhang, Tianyan Wang, Gang Zheng, Xiaohu Hou, Jing Zhao, Cheng-Yi 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. We present concept-proving data that these problems could be bypassed by using an enhanced nonviral DNA vector minicircle (MC) to produce BsAb in vivo. We found that the anti-CD3/CD20 produced from the minicircle (MC...
November 1, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27802778/transplantation-of-adipose-tissue-derived-mesenchymal-stem-cell-atmsc-expressing-alpha-1-antitrypsin-reduces-bone-loss-in-ovariectomized-osteoporosis-mice
#11
Mohammad Ahsanul Akbar, Yuanqing Lu, Ahmed S Elshikha, Mong-Jen Chen, Yuan Ye, Elizabeth M Whitley, Lexie Shannon Holliday, Chang Lung-Ji, Sihong Song
Osteoporosis is a common health problem severely affecting the life quality of many people, especially women. Current treatment options for osteoporosis are limited due to their association with several side-effects and moderate efficacy. Therefore, novel therapies for osteoporosis are needed. In this study, we tested the feasibility of adipose tissue-derived mesenchymal stem cell (ATMSC) based human AAT (hAAT) gene therapy for the prevention of bone loss in an ovariectomized (OVX) mouse model. Eight-week-old female C57BL6 mice underwent ovariectomy and treated with hAAT (protein therapy), ATMSC (stem cell therapy), ATMSC+hAAT (combination of ATMSC and hAAT therapy), ATMSCs infected with lentiviral vectors expressing hAAT (ATMSC based hAAT gene therapy)...
November 1, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27762639/stem-cells-for-modeling-and-therapy-of-parkinson-s-disease
#12
Qingxi Zhang, Wanling Chen, Sheng Tan, Tongxiang Lin
Parkinson's disease (PD) is the second most frequent neurodegenerative disease after Alzheimer's disease, which is characterized by low level of dopamine expressing in the striatum and deteriorated dopaminergic neurons (DAn) in Substantia nigra pars compacta (SNpc). Generation of PD-derived DAn including differentiation of human embryonic stem cell (hESC), human neural stem cell (hNSC), human induced pluripotent stem cell (hiPSC) and directly reprogramming provide an ideal tool to model PD, which created the possibilities of mimicking key essential pathological processes charactering single cell changes in vitro...
October 20, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27762627/mir-22-inhibits-cd34-cells-expansion-through-decreasing-%C3%AE-catenin-in-osteoblasts
#13
Yuxia Yang, Yanju Zhang, Zhenchuan Miao, Junhua Zhou, Jianyuan Luo
The bone marrow (BM) microenvironment, heavily composed of osteoblasts, plays a key role during the normal development of hematopoiesis. Endogenous miR-22 has an important function on the hematopoietic development and osteoblastic differentiation. It is unclear whether miR-22 in osteoblasts from the BM microenvironment also has an important function on the development of hematopoiesis. In this study, we found that the capacity of FBMOB-hTERT cells to expand human cord blood (CB) CD34+ cells and maintain the multipotency of CB CD34+ cells is decreased upon ectopic expression of miR-22...
October 20, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27758144/genetically-engineered-macrophages-a-potential-platform-for-cancer-immunotherapy
#14
Kara W Moyes, Nicole A P Lieberman, Shannon A Kreuser, Harrison Chinn, Conrad Winter, Gail Deutsch, Virginia Hoglund, Reid Watson, Courtney A Crane
In spite of their successes against hematologic malignancies, immunotherapeutic interventions for the treatment of patients with glioblastoma (GBM) have thus far been unsuccessful. This is in part due to the presence of a tumor microenvironment that fosters neoplastic growth and protects the tumor from destruction by the immune system. A novel genetically engineered macrophage-based platform has been developed with the potential to minimize the effects of the suppressive tumor microenvironment and improve innate and adaptive antitumor immune responses...
October 18, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27750461/evaluation-of-dose-and-safety-of-aav7m8-and-aav8bp2-in-the-non-human-primate-retina
#15
Pavitra Ramachandran, Vivian Lee, Zhangyong Wei, Ji Yun Song, Giulia Casal, Therese Cronin, Keirnan Willett, Rachel Huckfeldt, Jessica I W Morgan, Tomas S Aleman, Albert M Maguire, Jean Bennett
Within the next decade, we will see many gene therapy clinical trials for eye diseases progress, which may lead to treatments for thousands of visually impaired people around the world. To target retinal diseases that affect specific cell types, several recombinant adeno-associated virus (AAV) serotypes have been generated and used successfully in pre-clinical mouse studies. Because there are numerous anatomic, and physiologic differences between the eyes of mice and 'men' and because surgical delivery approaches and immunologic responses also differ between these species, we evaluated the transduction characteristics of two promising new serotypes AAV7m8 and AAV8BP2, in retinas of animals that are most similar to those of humans: non-human primates (NHPs)...
October 18, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27736201/aav-delivery-of-endothelin-1-shrna-attenuates-cold-induced-hypertension
#16
Peter Gin-Fu Chen, Zhongjie Sun
Cold temperatures are associated with increased prevalence of hypertension. Cold exposure increases endothelin-1 (ET1) production. The purpose of this study is to determine if upregulation of ET1 contributes to cold-induced hypertension (CIH). In vivo RNAi silencing of the ET1 gene was achieved by AAV2 delivery of ET1 short-hairpin siRNA (ET1-shRNA). Four groups of male rats were used. Three groups were given AAV.ET1-shRNA, AAV.SC-shRNA (scrambled shRNA), and phosphate-buffered saline (PBS), respectively, before exposure to a moderately cold environment (6...
October 12, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27710144/lentiviral-vector-gene-transfer-of-endostatin-angiostatin-for-macular-degeneration-gem-study
#17
Peter A Campochiaro, Andreas K Lauer, Elliott H Sohn, Tahreem A Mir, Stuart Naylor, Matthew C Anderton, Michelle Kelleher, Richard Harrop, Scott Ellis, Kyriacos A Mitrophanous
Neovascular age-related macular degeneration (NVAMD) is a prevalent cause of vision loss. Intraocular injections of VEGF-neutralizing proteins provide benefit, but many patients require frequent injections for a prolonged period. Benefits are often lost over time due to lapses in treatment. New treatments that sustain anti-angiogenic activity are needed. This study tested the safety and expression profile of a lentiviral Equine Infectious Anemia Virus (EIAV) vector expressing endostatin and angiostatin (RetinoStat(®))...
September 26, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27611239/lentivirus-mediated-correction-of-artemis-deficient-severe-combined-immunodeficiency
#18
Divya Punwani, Misako Kawahara, Jason Yu, Ukina Sanford, Sushmita Roy, Kiran Patel, Denise A Carbonaro, Andrea D Karlen, Sara Khan, Kenneth G Cornetta, Michael Rothe, Axel Schambach, Donald B Kohn, Harry L Malech, R Scott McIvor, Jennifer M Puck, Morton J Cowan
During B and T lymphocyte maturation, V(D)J recombination is initiated by creation of DNA double-strand breaks. Artemis is an exonuclease essential for their subsequent repair by non-homologous end-joining. Mutations in DCLRE1C, the gene encoding Artemis, cause T-B-NK+ severe combined immunodeficiency (ART-SCID) and also confer heightened sensitivity to ionizing radiation and alkylating chemotherapy. Although allogeneic hematopoietic cell transplantation (HCT) can treat ART-SCID, conditioning regimens are poorly tolerated, leading to early mortality and/or late complications, including short stature, endocrinopathies, and dental aplasia...
September 9, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27762630/enhancing-graduate-and-postdoctoral-education-to-create-a-sustainable-biomedical-workforce
#19
Cynthia N Fuhrmann
PhD-trained biomedical scientists are moving into an increasingly diverse variety of careers within the sciences. However, graduate and postdoctoral training programs have historically focused on academic career preparation, and have not sufficiently prepared trainees for transitioning into other scientific careers. Advocates for science have raised the concern that the collective disregard of the broader career-development needs for predoctoral and postdoctoral trainees could drive talent away from science in upcoming generations...
November 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27749100/changing-the-face-of-modern-medicine-stem-cells-and-gene-therapy-abstract-author-index
#20
(no author information available yet)
No abstract text is available yet for this article.
November 2016: Human Gene Therapy
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