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Human Gene Therapy

Alice Moussy, Nan Papili-Gao, Guillaume Corre, Valentina Poletti, Saliha Majdoul, David Fenard, Rudiyanto Gunawan, Daniel Stockholm, Andras Paldi
The initial stages following the in vitro cytokine stimulation of human cord blood CD34+ cells overlap with the period when lentiviral gene transfer is typically performed. We used single-cell transcriptional profiling and time-lapse microscopy to investigate how the vector-cell crosstalk impacts on the fate decision process. We analyzed the single-cell transcription profiles using a new algorithm and show that lentiviral transduction during the early stages of stimulation modifies the dynamics of the fate choice process of the CD34+ cells...
April 12, 2019: Human Gene Therapy
Yanliang Yuan, Bing Huang, Haoran Miao, Xiucheng Liu, Hao Zhang, Fan Qiu, Zhiwei Liu, Yiqian Zhang, Hongyan Dong, Zhongming Zhang
The failure to maintain the viability of ischemic myocardium is one of the mechanisms that causes ischemic heart dysfunction after revascularization. Hibernating myocardium is considered to be able to maintain long-term viability during chronic hypoperfusion. Pigment epithelium-derived factor (PEDF) decreases the contractility of hypoxic cardiomyocytes and protects cardiomyocytes against ischemic injury, which is strikingly similar to the pathophysiologic characteristics of hibernating myocardium. It was therefore postulated that PEDF may induce acute ischemic myocardium into a "hibernating-like" state to maintain its viability...
March 29, 2019: Human Gene Therapy
Guo-Qing Li, Yu-Xuan Fang, Ying Liu, Fan-Ru Meng, Xia Wu, Chun-Wang Zhang, Yu Zhang, Dan Liu, Bo Gao
Fibroblast-like synoviocytes (FLSs) participate in the pathogenesis of rheumatoid arthritis (RA). Emerging evidence has highlighted the role of long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) and its potential involvement in RA. In this study, we test the hypothesis that the MALAT1 might inhibit proliferation and inflammatory response of FLSs in RA. The expression of MALAT1 was examined in synovial tissues from patients with RA. The effect of MALAT1 on cultured FLSs was analyzed by introducing overexpressed MALAT1 or shRNA against MALAT1...
March 26, 2019: Human Gene Therapy
Raquel Cabrera-Pérez, Ferran Vila-Julia, Michio Hirano, Federico Mingozzi, Javier Torres-Torronteras, Ramon Marti
MNGIE (mitochondrial neurogastrointestinal encephalomyopathy) is a devastating disease caused by mutations in TYMP, encoding thymidine phosphorylase (TP). In MNGIE patients, TP dysfunction results in systemic thymidine and deoxyuridine overload, which interferes with mitochondrial DNA replication. Preclinical studies have shown that gene therapy using a lentiviral vector targeted to hematopoietic stem cells or an adeno-associated vector (AAV) transcriptionally targeted to liver are feasible approaches to treat MNGIE...
March 22, 2019: Human Gene Therapy
Hakan Akbulut, Arzu Cöleri, Gunce Sahin, Yucheng Tang, Fikri Icli
The combination of cytotoxic treatment modalities including oncolytic viral gene therapies and immunotherapy usually yields a synergistic effect. In the current study, we constructed a bicistronic adenoviral vector, Ad-CD-GMCSF, carrying the cytosine deaminase (CD) and granulocyte macrophage-colony stimulating factor (GM-CSF) transcription units driven by a CMV promoter and tested the in vitro efficacy of the vector in tumor cell lines and a syngeneic mouse model of colon cancer. The tumor cells infected with Ad-CD-GMCSF vector were found to produce a substantial amount of GM-CSF tumor cell lines...
March 20, 2019: Human Gene Therapy
Roy L Kao, Laurel C Truscott, Tzu-Ting Chiou, Wenting Tsai, Anna M Wu, Satiro N De Oliveira
BACKGROUND: We propose using gene-modification of HSC to create persistent generation of multilineage immune effectors to directly target cancer cells. Gene-modified human hematopoietic stem cells (HSC) have been used to introduce genes to correct, prevent or treat diseases. Concerns regarding malignant transformation, abnormal hematopoiesis and autoimmunity exist, making the co-delivery of a suicide gene a necessary safety measure. We tested truncated epidermal growth factor receptor (EGFRt) as a suicide gene system co-delivered with anti-CD19 chimeric antigen receptor (CAR) to human HSC...
March 12, 2019: Human Gene Therapy
Nina N Schommer, Jacklyn Nguyen, Bryan S Yung, Katherine Schultheis, Kar Muthumani, David Weiner, Laurent Humeau, Kate E Broderick, Trevor R F Smith
Plasmid DNA (pDNA) gene delivery is a highly versatile technology which has the potential to address a multitude of unmet medical needs. Advances in the pDNA delivery to host tissue with the employment of in vivo electroporation (EP) has led to significantly enhanced gene expression leading to the recent demonstration of clinical efficacy with the platform. Building upon this platform, we report enzyme-mediated modification of the muscle tissue extracellular matrix structure at the site of pDNA delivery operates in a synergistic manner with EP to further enhance both local and systemic gene expression...
March 12, 2019: Human Gene Therapy
Karine Sii-Felice, Javier Castillo Padilla, Francis Relouzat, Joëlle Cheuzeville, Siriporn Tantawet, Leila Maouche-Chretien, Roger Le Grand, Philippe Leboulch, Emmanuel Payen
Recent marketing approval for genetically engineered hematopoietic stem and T cells bears witness to the substantial improvements in lentiviral vectors over the last two decades, but evaluations of the long-term efficacy and toxicity of gene and cell therapy products will, nevertheless, require further studies in nonhuman primate models. <i>Macaca fascicularis</i> monkeys from Mauritius have a low genetic diversity and are particularly useful for reproducible drug testing. In particular, they have a genetically homogeneous class I MHC system that probably mitigates the variability of the response to simian immunodeficiency virus infection...
March 8, 2019: Human Gene Therapy
Ying Miao, Ling-Fei Zhang, Min Zhang, Rui Guo, Mo-Fang Liu, Biao Li
Poorly differentiated thyroid carcinoma cells tend to be more aggressive and show enhanced glucose uptake which could be exploited for anti-cancer strategy. Previously, we identified hexokinase2 (HK2) as a direct target of miR-143. In our current study, the effects of miR-143 on glucose metabolism and tumor biological behavior were investigated in FTC-133 cells which is a poorly differentiated thyroid carcinoma (PDTC). Additionally, tumor-bearing mice xenografts of PDTC were constructed, with encapsulated miR-143 agomir being administered intravenously...
March 8, 2019: Human Gene Therapy
Jerry R Mendell, Louis G Chicoine, Samiah A Al-Zaidy, Zarife Sahenk, Kelly Lehman, Linda Lowes, Natalie Miller, Lindsay Alfano, Beverly Galliers, Sarah Lewis, Darren Murrey, Ellyn L Peterson, Danielle A Griffin, Kathleen Church, Sharon Cheatham, John P Cheatham, Mark J Hogan, Louise R Rodino-Klapac
(Word Count 280) In a previous LGMD2D clinical trial, robust alpha-sarcoglycan (αSG) gene expression was confirmed following intramuscular gene (SGCA) transfer. This paved the way for first in-human isolated limb infusion (ILI) gene transfer trial to the lower limbs. Delivery of scAAVrh74.tMCK.hSGCA via an intravascular route through the femoral artery predicted improved ambulation. This method was initially chosen to avoid safety concerns required for large systemic vascular delivery viral loads. We adopted ILI methods from the extensive chemotherapy experience for treatment of malignancies confined to the extremity...
March 6, 2019: Human Gene Therapy
Mickaël Guilbaud, Marie Devaux, Célia Couzinié, Johanne Le Duff, Alice Toromanoff, Celine Vandamme, Nicolas Jaulin, Gwladys Gernoux, Thibaut Larcher, Philippe Moullier, Caroline Le Guiner, Oumeya Adjali
Anti-transgene immune responses elicited after intramuscular (IM) delivery of recombinant Adeno-Associated Viruses (rAAV) have been shown to hamper long-term transgene expression in large animal models of rAAV-mediated gene transfer. To overcome this hurdle, we and others described an alternative mode of delivery of rAAV vectors in nonhuman primate muscles: the locoregional intravenous route of administration (LR). Using this injection mode, we previously reported in cynomolgus monkeys a persistent inducible transgene expression for at least 1 year under the control of the tetracycline-inducible TetON system, with no immunity against the rtTA transgene product...
February 27, 2019: Human Gene Therapy
Jifan Guo, Wenping Song, Joseph Boulanger, Ethan Y Xu, Fang Wang, Yanqin Zhang, Qun He, Suxia Wang, Li Yang, Cynthia Pryce, Lucy Phillips, Deidre MacKenna, Ekkehard Leberer, Oxana Ibraghimov-Beskrovnaya, Jie Ding, Shiguang Liu
BACKGROUND: Alport syndrome is a genetic disease caused by mutations in type IV collagen and characterized by progressive kidney disease. The Col4α3-/- mouse model recapitulates main features of human Alport syndrome. Previously, we have reported that kidney microRNA-21 (miR-21) expression is significantly increased in Col4α3-/- mice and administration of anti-miR-21 oligonucleotides (anti-miR-21) attenuates kidney disease progression in Col4α3-/- mice, indicating that miR-21 is a viable therapeutic target for Alport syndrome...
February 27, 2019: Human Gene Therapy
Mavis Agbandje-McKenna, Arun Srivastava
No abstract text is available yet for this article.
February 26, 2019: Human Gene Therapy
Sangoh Han, Songtao Li, Jeffrey I Everitt, Dwight Koeberl
Gene therapy for Pompe disease with adeno-associated virus (AAV) vectors has advanced into early phase clinical trials. However, the paucity of cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle, where it is needed to take up acid α-glucosidase (GAA), has impeded the efficacy of Pompe disease gene therapy. Long-acting selective β2 receptor agonists previously enhanced the CI-MPR expression in muscle. In this study we have evaluated the selective ββ2 agonist salmeterol in GAA knockout (KO) mice in combination with an adeno-associated virus (AAV) vector expressing human GAA specifically in the liver...
February 26, 2019: Human Gene Therapy
Nalinda B Wasala, Chady H Hakim, Shi-Jie Chen, N Nora Yang, Dongsheng Duan
Clustered regularly interspaced short palindromic repeats (CRISPR) editing is being considered as a potential gene repair therapy to treat Duchenne muscular dystrophy, a dystrophin-deficient lethal muscle disease affecting all muscles in the body. A recent preliminary study from the Olson laboratory (Amoasii et al. Science 2018;362:89-91) showed robust dystrophin restoration in a canine Duchenne muscular dystrophy model following intramuscular or intravenous delivery of the CRISPR editing machinery by adeno-associated virus serotype 9...
February 26, 2019: Human Gene Therapy
Stefan Pellenz, Michael Phelps, Weiliang Tang, Blake T Hovde, Ryan B Sinit, Wenqing Fu, Hui Li, Eleanor Chen, Raymond J Monnat
We have identified 35 new sites for targeted transgene insertion that have the potential to serve as new human genomic 'safe harbor' sites. 'Safe harbor' site potential for these 35 sites, located on 16 chromosomes including both arms of the human X chromosome, and for the existing human 'safe harbor' sites AAVS1, hROSA26 and CCR5 was assessed using 8 different desirable, widely accepted criteria for 'safe harbor' sites verifiable with human genomic data. Three representative newly identified sites on human chromosomes 2 and 4 were then experimentally validated by in vitro and in vivo cleavage-sensitivity tests, and analyzed for population-level and cell line-specific sequence variants that might confound site targeting...
February 22, 2019: Human Gene Therapy
Leonardo Chicaybam, Luiza de Macedo Abdo, Mayra Carneiro, Bárbara Costa Peixoto, Mariana Duarte Viegas, Priscila de Sousa Ferreira, Marcia Fornazim, Maria Spago, Angelo Brunelli Albertoni Laranjeira, Pedro Octavio de Campos-Lima, Alexandre Nowill, Luciana Rodrigues Carvalho Barros, Martin Bonamino
CAR T cell immunotherapy for the treatment of cancer is now an approved treatment for B-cell malignancies. However, the use of viral vectors to provide long-term CAR expression is associated with high production costs and cumbersome quality controls, impacting the final cost of CAR-T cell therapies. Non-viral integrative vectors such as Sleeping Beauty (SB) transposons provide an alternative to modify primary T cells. Therefore, we developed a protocol to expand SB-transfected 19BBζ CAR T cells using a lymphoblastoid cell line (LCL), and evaluated T cell phenotype as well as function along the T cell expansion...
February 22, 2019: Human Gene Therapy
Hongyan Liu, Zhuozhuang Lu, Xin Zhang, Xiaojuan Guo, Lingling Mei, Xiaohui Zou, Yuxu Zhong, Min Wang, Tao Hung
Existing adenoviral vector systems have two drawbacks. It is labor-intensive and time-consuming to load a transgene in these systems, and transgene harboring vectors are dead ends: they cannot be reused to construct a vector carrying another transgene or achieving new characteristics. To conquer these shortcomings, we constructed single plasmid-based adenoviral vector systems where a unique PmeI site was located at the position for insertion of exogenous gene. PCR amplified transgene could be cloned into PmeI-linearized start plasmids by one step of Gibson assembly to generate target adenoviral plasmids, which were then ready for virus rescue...
February 22, 2019: Human Gene Therapy
Magdalena M Zak, Polyxeni Gkontra, Cristina Clemente, Mario Leonardo Squadrito, Alessia Ferrarini, Ruben A Mota, Eduardo Oliver, Susana Rocha, Jaume Aguero, Jesus Vazquez, Michele De Palma, Borja Ibañez, Alicia G Arroyo
Microvascular dysfunction and resulting tissue hypoxia is a major contributor to the pathogenesis and evolution of cardiovascular diseases (CVD). Diverse gene and cell therapies have been proposed to preserve the microvasculature or boost angiogenesis in CVD with moderate benefit. In this study, we tested in vivo the impact of sequential delivery by bone marrow cells of the pro-angiogenic factors vascular endothelial growth factor (VEGFA) and sphingosine-1-phosphate (S1P) in a myocardial infarction model. For that we transduced mouse bone marrow cells with lentiviral vectors coding for VEGFA or sphingosine kinase (SPHK1), which catalyzes S1P production, and injected them intravenously 4 and 7 days after cardiac ischemia/reperfusion in mice...
February 21, 2019: Human Gene Therapy
Sofia Bougioukli, Biagio Saitta, Osamu Sugiyama, Amy Tang, Joseph Elphingstone, Denis Evseenko, Jay R Lieberman
Umbilical cord blood (UCB) has been increasingly explored as an alternative source of stem cells for use in regenerative medicine due to several advantages over other stem cell sources, including the need for less stringent HLA matching. Combined with an osteoinductive signal, UCB-MSCs could revolutionize the treatment of challenging bone defects. In this study we aimed to develop an ex vivo regional gene therapy strategy using BMP-2-transduced allogeneic UCB-MSCs to promote bone repair. To this end, human UCB-MSCs were transduced with a lentiviral vector carrying the cDNA for BMP-2 (LV-BMP-2)...
February 16, 2019: Human Gene Therapy
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