Abstract:
:Recombinant adeno-associated virus serotype 2 (rAAV2)-based human gene therapy for cystic fibrosis has progressed through a series of preclinical studies and phase I and II clinical trials. This agent has shown an encouraging safety profile, consistent levels of DNA transfer, and positive evidence of short-term clinical improvement in lung function in a prospective, placebo-controlled phase II trial of aerosol administration. Nonetheless, it has been difficult to assess the relationship between its molecular action and the observed clinical improvements, because of the lack of positive results from a highly specific assay for vector mRNA. This issue is further complicated by the fact that the clinical vector utilizes a small cryptic rAAV2 promoter sequence that is less robust for mRNA expression than typical viral promoters. In this paper, we report the results of more sensitive assays performed on primary nasal cells harvested from rAAV2-CFTR gene therapy recipients. These studies demonstrate a correlation between the presence of rAAV2-CFTR vector genomes, CFTR mRNA expression, and cAMP-activated chloride channel function in these cells. The observation of sizeable physiological correction in the face of low mRNA levels may reflect the regulatory role of low levels of CFTR protein as an activator of other chloride channels.
journal_name
Hum Gene Therjournal_title
Human gene therapyauthors
Flotte TR,Schwiebert EM,Zeitlin PL,Carter BJ,Guggino WBdoi
10.1089/hum.2005.16.921keywords:
subject
Has Abstractpub_date
2005-08-01 00:00:00pages
921-8issue
8eissn
1043-0342issn
1557-7422journal_volume
16pub_type
临床试验,杂志文章abstract::Systemic administration of adenoviral vectors leads to activation of innate and antigen-specific immunity. In an attempt to diminish T and B cell-specific immune responses to E1-deleted adenoviral vectors, capsid proteins were modified with various activated monomethoxypolyethylene glycols (MPEGs). The impact of this ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303402760372972
更新日期:2002-10-10 00:00:00
abstract::Gene therapy has evolved into a tempting strategy for the management of cancer and other life-threatening diseases. Various approaches employ retroviral vectors to deliver the therapeutic gene. The profound knowledge about retrovirus biology allows the generation of increasingly advanced vector systems as well as an a...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2007.071
更新日期:2008-01-01 00:00:00
abstract::The first report of in vivo gene delivery to the retina dates back to 1987 when a retroviral vector was injected intraocularly in newborn mice. Later came the observation that retinal cells could be successfully transduced using adenoviral and then adeno-associated and lentiviral vectors. By 2000, it had become clear ...
journal_title:Human gene therapy
pub_type: 杂志文章,评审
doi:10.1089/hum.2017.164
更新日期:2017-11-01 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::Hemophilia arthropathy (HA) represents the majority of morbidity in severe hemophilia patients, especially in resource-limited countries. Adeno-associated virus (AAV)-mediated gene therapy is showing promise for managing hemophilia. However, patients with neutralizing antibodies (NAbs) against AAV, and inhibitors to c...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2019.355
更新日期:2020-04-01 00:00:00
abstract::We reported total correction of blood coagulation plasma factor VIII (FVIII) activity, using adeno-associated virus serotype 8 (AAV8) vectors for liver-specific gene transfer in hemophilia A mice. We now show, irrespective of immunosuppression or route of administration, total long-term correction of hemophilia A mice...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2006.17.427
更新日期:2006-04-01 00:00:00
abstract::At present, much more studies have focused on the role of microRNAs in osteoporosis, but the more specific role of microRNA-150-3p (miR-150-3p) in osteoporosis still needs full exploration. We aim at investigating the role of miR-150-3p in osteoporosis and at exploring the related mechanisms. Bone marrow mesenchymal s...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2020.005
更新日期:2021-01-22 00:00:00
abstract::Previous studies have documented that the skin can be used as a bioreactor to produce proteins for systemic release to treat diseases. A gene-switch system has been developed that allows regulated expression of therapeutic genes. To determine whether this system could be used in the skin, we developed a transgenic mou...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303402753812476
更新日期:2002-06-10 00:00:00
abstract::Kallistatin is a serine proteinase inhibitor that has been shown to reduce joint swelling and to inhibit inflammation in a rat model of arthritis. In this study, we investigated the effect and mechanisms of kallistatin on cardiac function after myocardial ischemia-reperfusion (I/R) injury. The human kallistatin gene i...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2006.17.1201
更新日期:2006-12-01 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::Current clinical gene therapy protocols for the treatment of human immunodeficiency virus type 1 (HIV-1) infection often involve the ex vivo transduction and expansion of CD4+ T cells derived from HIV-positive patients at a late stage in their disease (CD4 count <400). These protocols involve the transduction of T cel...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1998.9.4-487
更新日期:1998-03-01 00:00:00
abstract::Genetically modified lymphoblastoid cell lines (LCL) have been shown to be an attractive alternative source of antigen-presenting cells for cancer vaccination in vitro. We tested their application in patients with pancreatic cancer in a phase I clinical trial. As a model tumor antigen, we selected the point-mutated (c...
journal_title:Human gene therapy
pub_type: 临床试验,杂志文章
doi:10.1089/hum.2011.153
更新日期:2012-12-01 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::Cell therapies are treatments in which stem or progenitor cells are stimulated to differentiate into specialized cells able to home to and repair damaged tissues. After their discovery, endothelial progenitor cells (EPCs) stimulated worldwide interest as possible vehicles to perform autologous cell therapy of tumors. ...
journal_title:Human gene therapy
pub_type: 杂志文章,评审
doi:10.1089/hum.2016.066
更新日期:2016-10-01 00:00:00
abstract::Human hematopoietic stem cells (HSCs) are poorly transduced by vectors based on adenovirus serotype 5 (Ad5). This is primarily due to the paucity of the coxsackievirus-Ad receptor on these cells. In an attempt to change the tropism of Ad5, we constructed a series of chimeric E1-deleted Ad5 vectors in which the shaft a...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303401753204562
更新日期:2001-11-01 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::Recombinant vectors based on adeno-associated virus serotype 8 (AAV8) have been successfully used in the clinic and hold great promise for liver-directed gene therapy. Preexisting immunity against AAV8 or the development of antibodies against the therapeutic transgene product might negatively affect the outcomes of ge...
journal_title:Human gene therapy
pub_type: 杂志文章,多中心研究
doi:10.1089/hum.2014.109
更新日期:2015-03-01 00:00:00
abstract::We evaluated the efficiency of gene transduction and of gene expression by adenoviral vectors in human lung adenocarcinoma cells. Freshly isolated cancer cells were collected from pleural effusions in adenocarcinoma patients by centrifugation with a Percoll gradient. Adenoviral vectors resulted in effective gene trans...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1997.8.1-1
更新日期:1997-01-01 00:00:00
abstract::Chronic inflammation in tibialis anterior muscles of mdx mice was produced by a single injection of a recombinant adenovirus vector (AV) expressing an immunogenic beta-galactosidase (beta-gal). In regions of intense beta-gal staining, mononuclear infiltrates abounded, and muscle fibers showed strong extrasynaptic utro...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2005.16.489
更新日期:2005-04-01 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::Immunologically sensitized recipients present one of the most critical problems in clinical organ transplantation today, since preformed antibodies rapidly destroy donor tissue expressing specific MHC class I antigens (Ag). Therefore, sensitized patients are either unable to receive a compatible organ, or experience a...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340050015923
更新日期:2000-02-10 00:00:00
abstract::Silencing of Wnt antagonists with aberrant activation of Wnt signaling is a common phenomenon in various human cancers. Wnt inhibitory factor-1 (WIF-1) is a secreted antagonist of Wnt signaling and acts through direct binding to Wnt in the extracellular space. In this study, we tried to illuminate the impact of WIF-1 ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2006.005
更新日期:2007-04-01 00:00:00
abstract::Williams-Beuren syndrome (WBS) and supravalvular aortic stenosis (SVAS) are genetic syndromes marked by the propensity to develop severe vascular stenoses. Vascular lesions in both syndromes are caused by haploinsufficiency of the elastin gene. We used these distinct genetic syndromes as models to evaluate the feasibi...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2011.201
更新日期:2012-11-01 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::Severe fetal growth restriction (FGR) affects 1:500 pregnancies, is untreatable and causes serious neonatal morbidity and death. Reduced uterine blood flow (UBF) and lack of bioavailable VEGF due to placental insufficiency is a major cause. Transduction of uterine arteries in normal or FGR sheep and guinea pigs using ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2020.006
更新日期:2020-11-01 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
abstract::DNA expression vectors may be administered to patients like conventional medicines to have a finite and controlled duration of action. The clinical application of these medicines will require a precise understanding of the kinetics of the administered gene, the mRNA transcript, and the gene product. The apparent kinet...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1994.5.6-679
更新日期:1994-06-01 00:00:00
abstract::Airway infiltration by eosinophils is a major characteristic of chronic asthma. CCL11 (eotaxin-1) is secreted by lung epithelial cells and functions as the major chemokine for eosinophil recruitment. Pseudotyped adeno-associated virus (AAV) 2/9, composed by the AAV2 rep and AAV9 cap genes, can efficiently target lung ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2012.012
更新日期:2012-11-01 00:00:00
abstract::Evaluation of the potential role of dendritic cells (DCs) as adjuvants for tumor vaccination has focused primarily on techniques that load DCs with peptide tumor antigens. Our aim has been to optimize the induction of antitumor immunity by enhancing the ability of DCs to present tumor-associated antigens endogenously ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1997.8.11-1355
更新日期:1997-07-20 00:00:00
abstract::Direct arterial gene transfer has been previously achieved using double-balloon catheters and perforated balloons, in most cases facilitated by the use of cationic liposomes or viral vectors. These gene delivery systems, however, have been compromised by issues relating to efficacy and/or safety, and furthermore requi...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1993.4.6-749
更新日期:1993-12-01 00:00:00