Abstract:
:Replication-deficient adenoviruses are known to induce acute injury and inflammation of infected tissues, thus limiting their use for human gene therapy. However, molecular mechanisms triggering this response have not been fully defined. To characterize this response, chemokine expression was evaluated in DBA/2 mice following the intravenous administration of various adenoviral vectors. Administration of adCMVbeta gal, adCMV-GFP, or FG140 intravenously rapidly induced a consistent pattern of C-X-C and C-C chemokine expression in mouse liver in a dose-dependent fashion. One hour following infection with 10(10) PFU of adCMVbeta gal, hepatic levels of MIP-2 mRNA were increased >60-fold over baseline. MCP-1 and IP-10 mRNA levels were also increased immediately following infection with various adenoviral vectors, peaking at 6 hr with >25- and >100-fold expression, respectively. Early induction of RANTES and MIP-1beta mRNA by adenoviral vectors also occurred, but to a lesser degree. The induction of chemokines occurred independently of viral gene expression since psoralen-inactivated adenoviral particles produced an identical pattern of chemokine gene transcription within the first 16 hr of administration. The expression of chemokines correlated as expected with the influx of neutrophils and CD11b+ cells into the livers of infected animals. At high titers, all adenoviral vectors caused significant hepatic necrosis and apoptosis following systemic administration to DBA/2 mice. To investigate the role of neutrophils in this adenovirus-induced hepatic injury, animals were pretreated with neutralizing anti-MIP-2 antibodies or depleted of neutrophils. MIP-2 antagonism and neutrophil depletion both resulted in reduced serum ALT/AST levels and attenuation of the adenovirus-induced hepatic injury histologically, confirming that this early injury is largely due to chemokine production and neutrophil recruitment. Our findings further clarify the early immune response against replication-deficient adenoviral vectors and suggest a strategy to prevent adenovirus-mediated inflammation and tissue injury by interfering with chemokine or neutrophil function.
journal_name
Hum Gene Therjournal_title
Human gene therapyauthors
Muruve DA,Barnes MJ,Stillman IE,Libermann TAdoi
10.1089/10430349950018364keywords:
subject
Has Abstractpub_date
1999-04-10 00:00:00pages
965-76issue
6eissn
1043-0342issn
1557-7422journal_volume
10pub_type
杂志文章abstract::Mucopolysaccharidosis type II (MPS II) is a neuropathic lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS), which leads to the accumulation of glycosaminoglycans (GAGs). We demonstrated that biochemical alterations in the brains of MPS II mice are not corrected by bone marrow transplantat...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2014.158
更新日期:2015-06-01 00:00:00
abstract::La Crosse virus (LACV)-mediated encephalitis is the most frequently reported arboviral disease in the United States, but to date no vaccine against this virus is available. We have established a new animal model, genetically targeted mice lacking a functional interferon type I receptor (IFNAR-1). These mice show an ag...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430349950017653
更新日期:1999-07-01 00:00:00
abstract::pZIG(hGCSFR) is a retroviral vector that can co-express two genes and also provides alternative selection markers. This retroviral vector has been constructed to incorporate an internal ribosome entry site (IRES) element to co-express two exogenous genes in mammalian cells. Two marker/selection genes have been cloned ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1997.8.8-979
更新日期:1997-05-20 00:00:00
abstract::Eleven patients with moderate to severe erectile dysfunction (ED) were given a single-dose corpus cavernosum injection of hMaxi-K, a "naked" DNA plasmid carrying the human cDNA encoding hSlo (for human slow-poke), the gene for the alpha, or pore-forming, subunit of the human smooth muscle Maxi-K channel. Three patient...
journal_title:Human gene therapy
pub_type: 杂志文章,多中心研究
doi:10.1089/hum.2006.17.1165
更新日期:2006-12-01 00:00:00
abstract::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. A...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2016.154
更新日期:2016-11-01 00:00:00
abstract::Three dogs with deficiency of the lysosomal enzyme alpha-L-iduronidase were treated by gene replacement therapy targeted at muscle. Direct intramuscular injections of plasmid encoding the alpha-L-iduronidase gene cDNA resulted in no detectable enzyme production, but may have resulted in immunologic sensitization to id...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1996.7.13-1595
更新日期:1996-08-20 00:00:00
abstract::Replication-deficient viral vectors are currently being used in gene transfer strategies to treat cancer cells. Unfortunately, viruses are limited in their ability to diffuse through tissue. This makes it virtually impossible to infect the majority of tumor cells in vivo and results in inadequate gene transfer. This p...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1998.9.8-1209
更新日期:1998-05-20 00:00:00
abstract::Cell-based gene transfer using a stent platform would provide a significant advantage in terms of site-specific gene expression in the vasculature. The current study presents a novel stent design that allows stable in vivo transgene expression over a 4-week period in the vasculature. A mesh-stent coated with fibronect...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340252792567
更新日期:2002-02-10 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::Abstract Our studies have shown that coinjection of conventional single-stranded adeno-associated virus 2 (ssAAV2) vectors carrying the enhanced green fluorescent protein (EGFP) gene with self-complementary (sc) AAV2-T cell protein tyrosine phosphatase (TC-PTP) and scAAV2-protein phosphatase-5 (PP5) vectors resulted i...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2009.100
更新日期:2010-03-01 00:00:00
abstract::Glycogen storage disease type II (GSD-II) is a lethal, autosomal recessive metabolic myopathy caused by a lack of acid-alpha-glucosidase (GAA) activity in the cardiac and skeletal muscles. Absence of adequate intralysosomal GAA activity results in massive amounts of glycogen accumulation in multiple muscle groups, res...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303401750195917
更新日期:2001-05-20 00:00:00
abstract::Due to both the avascularity of the cornea and the relatively immune-privileged status of the eye, corneal transplantation is one of the most successful clinical transplant procedures. However, in high-risk patients, which account for >20% of the 180,000 transplants carried out worldwide each year, the rejection rate ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2017.184
更新日期:2018-06-01 00:00:00
abstract::Deficiencies in different steps of purine metabolism give rise to a number of human inherited disorders. Lesch-Nyhan syndrome is a severe neurological disorder, caused by a deficiency in the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT). HPRT-deficient mice have been generated, but have proved to...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1996.7.13-1491
更新日期:1996-08-20 00:00:00
abstract::Interleukin-12 (IL-12) is a heterodimeric cytokine that plays an important role in the development of cellular immunity. Clinical applications for this lymphokine include resolution of infectious disease, cancer immunotherapy, and boosting cellular immunity in AIDS patients. When using IL-12 and other cytokines therap...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1996.7.3-333
更新日期:1996-02-10 00:00:00
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 plasmi...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1998.9.5-729
更新日期:1998-03-20 00:00:00
abstract::The ability to control proliferation of grafted cells in the heart and consequent graft size could dramatically improve the efficacy of cell therapies for cardiac repair. To achieve targeted graft cell proliferation, we created a chimeric receptor (F36Vfgfr-1) composed of a modified FK506-binding protein (F36V) fused ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2006.161
更新日期:2007-05-01 00:00:00
abstract::Clinical trials of gene therapy using a viral delivery system for glioma have been limited. Recently, gene therapy using stem cells as the vehicles for delivery of therapeutic agents has emerged as a new treatment strategy for malignant brain tumors. In this study, we used human umbilical cord blood-derived mesenchyma...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2010.187
更新日期:2011-06-01 00:00:00
abstract::Dystrophic epidermolysis bullosa (DEB) comprises a family of inherited blistering skin disorders for which no corrective therapy currently exists. In the most severe form, the Hallopeau-Siemens subtype (RDEB-HS), the epidermal adhesion protein collagen VII is absent from the skin as a consequence of null mutations in ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340260201743
更新日期:2002-09-01 00:00:00
abstract::To evaluate the hypothesis that innate immune mechanisms play a major role in eliminating adenovirus (Ad) vectors from the lung, the fate of adenoviral genome of an Ad vector was quantified in the first 24 h after intratracheal administration of an Ad vector coding for beta-galactosidase (beta gal) to mice. Southern a...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1997.8.14-1675
更新日期:1997-09-20 00:00:00
abstract::Adenovirus-polylysine-DNA complexes were evaluated for their capacity to accomplish direct in vivo gene transfer to airway epithelium employing a rodent model. Binary complexes containing transferrin or adenovirus, or combination complexes containing both transferrin and adenovirus, were evaluated. The highest in vitr...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1993.4.1-17
更新日期:1993-02-01 00:00:00
abstract::Activation of T cells is necessary for efficient retroviral-mediated gene transfer. In addition, if the population of infused cells is to be limited to transduced cells, a means of positive selection is required. We describe a clinical scale procedure for activation of donor T cells with anti-CD3/CD28 beads followed b...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340252939087
更新日期:2002-05-20 00:00:00
abstract::Targeted vectors provide a number of advantages for systemic and local gene delivery strategies. Several groups have investigated the utility of using various ligands to alter the tropism of adenovirus (Ad) vectors. We have previously demonstrated that fibroblast growth factor (FGF) ligands can specifically target DNA...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340050016265
更新日期:2000-01-01 00:00:00
abstract::Glycogen storage disease type II (GSDII) is a lysosomal storage disease caused by a deficiency in acid alpha-glucosidase (GAA), and leads to cardiorespiratory failure by the age of 2 years. In this study, we investigate the impact of anti-GAA antibody formation on cross-correction of the heart, diaphragm, and hind-lim...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2005.16.68
更新日期:2005-01-01 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::The field of adenovirology is undergoing rapid change in response to increasing appreciation of the potential advantages of adenoviruses as the basis for new vaccines and as vectors for gene and cancer therapy. Substantial knowledge and understanding of adenoviruses at a molecular level has made their manipulation for...
journal_title:Human gene therapy
pub_type: 杂志文章,评审
doi:10.1089/hum.2013.235
更新日期:2014-04-01 00:00:00
abstract::Adenoviral vectors used in gene therapy are predominantly derived from adenovirus serotype 5 (Ad5), which infects a broad range of cells. Ad5 cell entry involves interactions with the coxsackie-adenovirus receptor (CAR) and integrins. To assess these receptors in vivo, we mutated amino acid residues in fiber and pento...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303403765255165
更新日期:2003-05-20 00:00:00
abstract::Malignant mesothelioma is a tumor of the pleura for which there is no satisfactory treatment. It is almost universally fatal, regardless of the stage of the tumor at the time of diagnosis. Current treatment modalities include surgery, chemotherapy, and radiation therapy, although in some series none of these modalitie...
journal_title:Human gene therapy
pub_type: 临床试验,杂志文章
doi:10.1089/hum.1998.9.17-2641
更新日期:1998-11-20 00:00:00
abstract::Stem cell mobilization to injured tissue contributes to neovascularization, resulting in regeneration after myocardial infarction (MI). We previously showed that direct cardiac injection of a recombinant lentivirus (LV) that engineers expression of membrane-bound stem cell factor (mSCF) improves outcomes immediately a...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2012.063
更新日期:2012-12-01 00:00:00
abstract::Gene transfer for therapeutic angiogenesis represents a novel treatment for patients with chronic angina refractory to standard medical therapy and not amenable to conventional revascularization. We sought to assess the role of intraoperative multiplane transesophageal echocardiography (MPTEE) in guiding injection of ...
journal_title:Human gene therapy
pub_type: 临床试验,杂志文章
doi:10.1089/10430349950016951
更新日期:1999-09-20 00:00:00
abstract::The inherited deficiency in adenosine deaminase (ADA), which results in severe combined immunodeficiency, is generally regarded as an optimal model for the development of human somatic gene therapy. The ideal target for the correction of ADA deficiency and other lympho-hematopoietic disorders would be the hematopoieti...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1991.2.3-203
更新日期:1991-10-01 00:00:00