Abstract:
:Previously, we described a nonviral cytoplasmic gene therapy vector system based on the T7 autogene concept. This system has been shown to achieve rapid and high levels of gene expression in a variety of animal cells and tissues. To test the utility of the system in vivo tumor ablation, a T7 cancer gene therapy plasmid vector, pT7T7/T7TK, was constructed. This nonviral vector contains a T7 autogene, T7T7, and a human herpes simplex virus thymidine kinase (HSV-TK) gene driven by a second T7 promoter (T7TK). When co-transfected with T7 RNA polymerase (T7 RNAP) into cultured human osteosarcoma 143B cells, abut 10-20% of the cells were found to express HSV-TK, and more than 90% of the cells were killed in the presence of 1 microM ganciclovir (GCV) within 4 days after DNA transfection. The increase in killing above the transfection frequency is due to a "bystander" effect among transfected and untransfected 143B cells. Direct injections of pT7T7/T7TK into 143B tumors grown in nude mice resulted in TK gene expression in tumor cells located near the injection sites as revealed by the immunohistochemical staining. Repeated tumor injections of the pT7T7/T7TK vector and intraperitoneal (i.p.) injections of GCV resulted in inhibition of tumor growth and in tumor shrinkage in 6 out of 10 treated nude mice. Three of those six tumors fully regressed shortly after the end of the GCV injections. All of the full tumor regressions were found to be permanent and no apparent tumor relapses were observed for the rest of the lives of the treated nude mice after the initial tumor ablations. These results, combined with the nonviral and rapid cytoplasmic gene expression features, suggest that the T7 vector may be a good candidate for cancer gene therapy and other medical and biological applications.
journal_name
Hum Gene Therjournal_title
Human gene therapyauthors
Chen X,Li Y,Xiong K,Aizicovici S,Xie Y,Zhu Q,Sturtz F,Shulok J,Snodgrass R,Wagner TE,Platika Ddoi
10.1089/hum.1998.9.5-729subject
Has Abstractpub_date
1998-03-20 00:00:00pages
729-36issue
5eissn
1043-0342issn
1557-7422journal_volume
9pub_type
杂志文章abstract::Skeletal muscle represents an attractive target tissue for adenoviral gene therapy to treat muscle disorders and as a production platform for systemic expression of therapeutic proteins. However, adenovirus serotype 5 vectors do not efficiently transduce adult muscle tissue. Here we evaluated whether capsid modificati...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2012.003
更新日期:2012-10-01 00:00:00
abstract::As efficient and less toxic virus-derived gene therapy vectors are developed, a pressing problem is to avoid immune response to the therapeutic gene product. Secreted therapeutic proteins potentially represent a special problem, as they are readily available to professional antigen-presenting cells throughout the body...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2006.036
更新日期:2007-12-01 00:00:00
abstract::The efficient and specific introduction of genes into cancer cells in vivo remains a major challenge for current gene therapy modalities. Peptides possess appropriate properties to serve as tumor-targeting agents. Thus, finding new cancer-selective peptides directing gene transfer to neoplastic cells by reducing trans...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2005.16.1267
更新日期:2005-11-01 00:00:00
abstract::Engineering gene therapy vectors to modulate the immune response is an important goal. In this regard, costimulation of T cells is a critical determinant in immune activation. The costimulatory molecule CD40, expressed on antigen-presenting cells, is thought to interact with CD40 ligand (CD40L) expressed on activated ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303401750214302
更新日期:2001-06-10 00:00:00
abstract::Tumor angiogenesis is a rate-limiting factor for tumor growth, and the endothelial cells of tumor vessels display specific features that can be exploited for the selective delivery of cancer therapeutics. To specifically target exogenous genes to angiogenic tumor vessels, we generated a panel of vesicular stomatitis v...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303403322168028
更新日期:2003-08-10 00:00:00
abstract::Recombinant adeno-associated virus (AAV)-based vectors expressing therapeutic gene products have shown great potential for human gene therapy. One major challenge for translation of promising research to clinical development is the manufacture of sufficient quantities of AAV vectors that meet stringent standards for p...
journal_title:Human gene therapy
pub_type: 杂志文章,评审
doi:10.1089/hum.2009.064
更新日期:2009-07-01 00:00:00
abstract::Gene therapy for Duchenne muscular dystrophy will likely require that the corrective dystrophin gene be delivered to a high fraction of muscle fibers in vivo. Because of the large size of the dystrophin cDNA, adenoviral (Ad) vectors have been developed for this application. However, Ad vectors transduce mature muscle ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2006.17.314
更新日期:2006-03-01 00:00:00
abstract::Gene transfer of reporter genes may trigger immune responses against the heterologous protein resulting in shortening of gene expression and inflammation. We generated transgenic rats expressing the lacZ gene under the control of the human immunodeficiency virus type 1 (HIV-1) long-terminal repeat (LTR) (HIV-lacZ) to ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303402760128603
更新日期:2002-07-20 00:00:00
abstract::Genome engineering has gone mainstream because of breakthroughs in defining and harnessing naturally occurring, customizable DNA recognition cursors (protein or RNA-guided). At present, most gene editing relies on these cursors to direct custom DNA endonucleases to a specific genomic sequence to induce a double-strand...
journal_title:Human gene therapy
pub_type: 杂志文章,评审
doi:10.1089/hum.2016.071
更新日期:2016-06-01 00:00:00
abstract::Systemic administration of currently manufactured viral stocks has not so far achieved sufficient circulating titers to allow therapeutic targeting of metastatic disease. This is due to low initial viral titers, immune inactivation, nonspecific adhesion, and loss of particles. One way to exploit the elegant molecular ...
journal_title:Human gene therapy
pub_type: 杂志文章,评审
doi:10.1089/104303402760128504
更新日期:2002-07-20 00:00:00
abstract::Bag-1 exerts powerful antiapoptotic effects by binding and stabilizing Bcl-2 and interacting with the tumor necrosis factor receptor type I-induced death signal. We examined the effects of overexpression of Bag-1 by ex vivo adenoviral gene transfer on cold (4 degrees C for 24 hr) ischemia/reperfusion (I/R) injury of r...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340260185120
更新日期:2002-08-10 00:00:00
abstract::Bone marrow mesenchymal stem cells (BMSCs) represent an important source of cells for tissue repair. The tropism of these cells to the sites of injury and tumors has been well established. Their tumor-homing properties make BMSCs good candidates as antitumor agent delivery vehicles. In this study, we showed that BMSCs...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2010.116
更新日期:2011-04-01 00:00:00
abstract::Accurate quantification of gene transfer (or gene correction) is a universal challenge in the field of gene therapy. In developing a clinical trial of lymphocyte gene therapy for Hunter syndrome (mucopolysaccharidosis type II), methods using Southern blot or automated DNA sequencing technology were employed, but found...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430349950016898
更新日期:1999-10-10 00:00:00
abstract::Subcutaneous vaccination therapy with glioma cells, which are retrovirally transduced to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF), has previously proven effective in C57BL/6 mice harboring intracerebral GL261 gliomas. However, clinical ex vivo gene therapy for human gliomas would be difficult,...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340050057503
更新日期:2000-07-01 00:00:00
abstract::RNA interference (RNAi) is an evolutionarily conserved mechanism of posttranscriptional gene-specific silencing. For in vivo applications, RNAi has been hampered until recently by inefficient delivery methods and by the transient nature of the gene suppression. Lentiviral vectors (LVs) hold great promise for gene ther...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303403322611809
更新日期:2003-12-10 00:00:00
abstract::The immunogenicity of adenovirus vectors remains a major obstacle to their safe and efficacious use for gene therapy. In order to identify T-cell epitopes directly from adenoviruses, four viral protein sequences were screened for the well-characterized 9-mer HLA-A2 binding motif. Peripheral blood mononuclear cells (PB...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303402320138952
更新日期:2002-07-01 00:00:00
abstract::Gene delivery via murine-based recombinant retroviral vectors is currently widely used in gene therapy clinical trials. The vectors are engineered to be replication defective by replacing the structural and nonstructural genes of a cloned infectious retrovirus with a therapeutic gene of interest. The retroviral partic...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1997.8.10-1231
更新日期:1997-07-01 00:00:00
abstract::CRISPR-based technology has been adapted to achieve a wide range of genome modifications including transcription regulation. The focus of this review is on the application of CRISPR-based platforms such as nuclease-deficient Cas9 and Cas12a, to achieve targeted gene activation. We review studies to date that have empl...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2020.241
更新日期:2021-01-15 00:00:00
abstract::Spinal muscular atrophy (SMA) is an autosomal recessive disease affecting ∼1 in 10,000 live births. The most striking component is the loss of α-motor neurons in the ventral horn of the spinal cord, resulting in progressive paralysis and eventually premature death. There is no current treatment paradigm other than sup...
journal_title:Human gene therapy
pub_type: 杂志文章,评审
doi:10.1089/hum.2012.225
更新日期:2013-05-01 00:00:00
abstract::Retinal ganglion cells (RGCs) play a key role in the pathogenesis and development of glaucoma. The present study aims to investigate the underlying mechanism of long noncoding RNA growth arrest-specific transcript 5 (GAS5) in glaucoma development through regulating the apoptosis of RGCs. Rat models of chronic glaucoma...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2019.056
更新日期:2019-12-01 00:00:00
abstract::Unlike oncoretroviruses, lentiviral vectors can insert large genes and can target both dividing and nondividing cells; thus they hold unique promise as gene transfer agents. To enhance target range, the native lentiviral envelope glycoprotein is replaced (pseudotyped) with vesicular stomatitis virus G (VSVG), and the ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340360464723
更新日期:2003-01-01 00:00:00
abstract::Development of multidrug resistance (MDR) is the major obstacle to successful cancer chemotherapy. We have developed Daudi human lymphoma cells that are 20-fold more resistant than the parent cell line to vincristine (VCR) by infecting cells with pHaMDR1/A retroviral vector (Daudi/MDR20). Three DNA sequences of anti-M...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430349950018175
更新日期:1999-05-01 00:00:00
abstract::Defined serum-free conditions have great conceptual advantages for the biological safety and standardization of clinical gene transfer into hematopoietic stem cells. In the only study reported to date, Sekhar et al. achieved low serum conditions by a complex concentration procedure of a retroviral supernatant initiall...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1998.9.6-771
更新日期:1998-04-10 00:00:00
abstract::Although replication-deficient adenoviruses can efficiently transfer genes to the salivary glands, the current vectors precipitate an immediate, transient decrease in salivary function. To study the cause of this salivary hypofunction, 10(6)-10(10) plaque-forming units (pfu) of the vector AdCMV beta gal were delivered...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1996.7.9-1085
更新日期:1996-06-10 00:00:00
abstract::Recombinant adeno-associated virus 2 (rAAV) vectors have been successfully used for sustained expression of therapeutic genes. The potential of using rAAV as a cancer vaccine vector and the impact of a bacterial plasmid adjuvant on this activity were investigated. C57BL/6 mice received a single intramuscular injection...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2004.15.856
更新日期:2004-09-01 00:00:00
abstract::Efficient and homogeneous gene transfer to cardiac myocytes is a major target in myocardial gene therapy. The aim of this study was to determine the conditions permitting efficient, homogeneous, adenovirus-mediated gene transfer to cardiac myocytes, with a view to application during coronary artery catheterization. Ge...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340050015329
更新日期:2000-05-01 00:00:00
abstract::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. Single-cell transcriptional profiling and time-lapse microscopy were used to investigate how the vector-cell crosstalk impacts on the fate decisio...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2019.009
更新日期:2019-08-01 00:00:00
abstract::Introduction of a new vaccine requires choosing a delivery system that provides safe administration and the desired level of immunogenicity. The safety, tolerability, and immunogenicity of three monthly 2.5-mg doses of a PfCSP DNA vaccine were evaluated in healthy volunteers as administered intramuscularly (IM) by nee...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340260201644
更新日期:2002-09-01 00:00:00
abstract::Production of clinical-grade gammaretroviral vectors for ex vivo gene delivery requires a scalable process that can rapidly generate large amounts of vector supernatant, clear large numbers of residual packaging cells with minimal decreases in vector titer, and satisfy all current regulatory guidelines regarding produ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2010.064
更新日期:2011-01-01 00:00:00
abstract::The efficiency of gene therapy strategies against cancer is limited by the poor distribution of the vectors in the malignant tissues. To solve this problem, a new generation of tumor-specific, conditionally replicative adenoviruses is being developed. To direct the replication of the virus to breast cancer, we have co...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340050143435
更新日期:2000-09-20 00:00:00