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At least 199 records · Page 11Linked to original sources

PubMed2004

Adeno-associated virus 2-mediated antiangiogenic cancer gene therapy: long-term efficacy of a vector encoding angiostatin and endostatin over vectors encoding a single factor.

Angiogenesis is characteristic of solid tumor growth and a surrogate marker for metastasis in many human cancers. Inhibition of tumor angiogenesis using antiangiogenic drugs and gene transfer approaches has suggested the potential of this form of therapy in controlling tumor growth. However, for long-term tumor-free survival by antiangiogenic therapy, the factors controlling tumor neovasculature need to be systemically maintained at stable therapeutic levels. Here we show sustained expression of the antiangiogenic factors angiostatin and endostatin as secretory proteins by recombinant adeno-associated virus 2 (rAAV)-mediated gene transfer. Both vectors provided significant protective efficacy in a mouse tumor xenograft model. Stable transgene persistence and systemic levels of both angiostatin and endostatin were confirmed by in situ hybridization of the vector-injected tissues and by serum ELISA measurements, respectively. Whereas treatment with rAAV containing either endostatin or angiostatin alone resulted in moderate to significant protection, the combination of endostatin and angiostatin gene transfer from a single vector resulted in a complete protection. These data suggest that AAV-mediated long-term expression of both endostatin and angiostatin may have clinical utility against recurrence of cancers after primary therapies and may represent rational adjuvant therapies in combination with radiation or chemotherapy.

Angiogenesis Inhibitors↗

PubMed2002

Vigilant vector: heart-specific promoter in an adeno-associated virus vector for cardioprotection.

Repeated bouts of ischemia in the heart lead to fibrosis and eventually to heart failure. Although certain genes, such as SOD or hemoxygenase and antisense to AT(1)R, ACE, and (beta(1)-AR can provide short-term protection of the heart from ischemia, there is no known mechanism for constantly responding to repeated incidences of ischemia. We hypothesized that a "vigilant vector," designed to be expressed specifically in the heart and switch on therapeutic genes only during hypoxia, would provide cardioprotection. To attain cardiac specificity, we inserted an MLC2v promoter into an adeno-associated virus (AAV) designed to deliver AS to AT(1)R and gfp. In in vitro experiments in cardiomyocytes (H9C2 cells), the MLC2v-AAV-gfp drove gene expression in all cells at levels comparable to a cytomegalovirus (CMV) promoter. In in vivo experiments, the rAAV-MLC2v-gfp was injected intravenously into mice or rats. Green fluorescence protein (GFP) DNA was located in kidney, heart (right and left ventricle), lung, adrenal and spleen. GFP mRNA, however, was expressed only in the heart and absent in other tissues. To switch on the rAAV transgene during ischemia, we inserted a hypoxia response element (HRE). This upregulates transcription when O(2) levels are low. Thus, there are 4 components to the vigilant vector; a gene switch (HRE), a heart-specific promoter (MLC2v), a therapeutic gene (AS-AT(1)R) and a reporter gene (gfp). To silence or lower basal level of expression while retaining specificity, we have reduced the length of the MLC2v promoter from 3 kb to 1775 bp or 281 bp. The truncated promoter is equally effective in heart specific expression. Preliminary studies with the rAAV-HRE-gfp in vitro show an increased expression in 1% O(2) in 4 to 6 hours. By adding additional hypoxia-inducible factor (HIFalpha) (5 microg), the MLC2v-gfp expression is increased by 4-fold in 1% O(2). Further amplification of the gene to 400-fold in 1% O(2) can be achieved with a double plasmid. The construct may serve as a prototype "vigilant vector" to switch on therapeutic genes in specific tissue with physiological signals.

Angiotensin Receptor Antagonists↗

PubMed2003

Dose finding with retroviral vectors: correlation of retroviral vector copy numbers in single cells with gene transfer efficiency in a cell population.

Retroviral vectors are commonly used in clinical gene therapy, but recent observations of insertional oncogene activation in preclinical and clinical settings have forced a discussion of their safety. Here we investigated the relationship between retroviral transduction efficiency in mass cultures and the actual number of integrated vector copies in single cells using K562 leukemia and primary CD34+ cells. We found an exponential increase of integration numbers correlated to gene transfer rates and a linear increase of expression levels with insertion frequency. On average we detected one vector insertion per transduced cell for a gene transfer of less than 30%, 3 for 60%, and approximately 9 for 90% (in K562). Clonal analysis revealed strikingly increased variations of both transgene copy numbers (more than 20-fold in primary cells) and expression levels associated with higher transduction. Therefore, limiting retroviral gene transfer to approximately 30% may be suggested to avoid generating clones containing multiple insertions.

Cell Culture Techniques↗

PubMed2007

In vivo administration of lentiviral vectors triggers a type I interferon response that restricts hepatocyte gene transfer and promotes vector clearance.

Liver gene transfer is a highly sought goal for the treatment of inherited and infectious diseases. Lentiviral vectors (LVs) have many desirable properties for hepatocyte-directed gene delivery, including the ability to integrate into nondividing cells. Unfortunately, upon systemic administration, LV transduces hepatocytes relatively inefficiently compared with nonparenchymal cells, and the duration of transgene expression is often limited by immune responses. Here, we investigated the role of innate antiviral responses in these events. We show that administration of LVs to mice triggers a rapid and transient IFNalphabeta response. This effect was dependent on functional vector particles, and in vitro challenge of antigen-presenting cells suggested that plasmacytoid dendritic cells initiated the response. Remarkably, when LVs were administered to animals that lack the capacity to respond to IFNalphabeta, there was a dramatic increase in hepatocyte transduction, and stable transgene expression was achieved. These findings indicate that, even in the setting of acute delivery of replication-defective vectors, IFNs effectively interfere with transduction in a cell-type-specific manner. Moreover, because disabling a single component of the innate/immune network was sufficient to establish persistent xenoantigen expression, our results raise the hope that the immunologic barriers to gene therapy are less insurmountable than expected.

Animals↗

PubMed2006

[Development of non-viral vector based on the quantitative comparison of intracellular trafficking with viral vector].

For the development of efficient gene vector, intracellular processes such as cellular uptake, endosomal release and nuclear delivery must be overcome. Viruses have also evolved and have developed sophisticated mechanisms for controlling intracellular trafficking for the efficient delivery of their genomes to nuclei in host cells for symbiosis. In the light of these mechanisms, various kinds of artificial devices have been developed to overcome the intracellular barriers. However, in the majority of studies, variation of the transfection activity before and after the modification of devices was evaluated, and intracellular trafficking remained unclear. Therefore, it is understand to recognize which of the intracellular barrier should be intensively improved to enhance the transfection activity. To clarify the rate-limited process in the current non-viral vector, we compared the intracellular trafficking between adenovirus and LipofectAMINE PLUS. As a result, we found that difference of the transfection efficiency between adenovirus and LipofectAMINE PLUS was dominantly derived from the differences on transcription activity. Therefore it is essential to consider the regulation of the intranuclear events to improve the transfection activity of artificial vector.

Active Transport, Cell Nucleus↗

PubMed2000

[Situation of Mepraia spinolai, a wild vector for Chagas disease in Chile, in relation to others vectors from the perspective of their feeding profile].

BACKGROUND: Three triatomine species, Triatoma infestans, Mepraia spinolai and Mepraia gajardoi, are vectors for Chagas disease in Chile. AIM: To compare the alimentary profile of Mepraia spinolai, the Chilean wild vector of Chagas disease, with that of the several other triatomines. MATERIAL AND METHODS: The alimentary profile of Mepraia spinolai was compared with that of other triatomines using cluster analysis (Q and R techniques) with the Jaccard index. RESULTS: Three basic groups of triatomines were identified: domestic, wild and specialists, such as P. coreodes and C. pilosa. Our wild vector M. spinolai was in an intermediate position between wild and domestic clusters, grouping with T. rubrovaria, T. sordida and P. megistus. The feeding sources, animals of the domestic and peri-domestic habitat and wild animals, corresponded to the clusters of the two groups. CONCLUSIONS: Mepraia spinolai, being a preponderantly wild species, approaches human dwellings and obtains food from domestic animals and eventually, from human blood (Rev Méd Chile 2000; 128: 1108-12).

Animals↗

PubMed2003

[Construction of vector plasmids for the Plectonema boryanum cyanobacterium and creation, on such basis, of the vector-host system].

The plasmid composition of the Plectonema boryanum Gom. Cyanobacterium, strain CALU 465, was analyzed. A small pSM1 plasmid, size 1.5, was chosen for genetic engineering. The physical map, constructed for the plasmid, was used to create the pSTS series, i.e. vector construction for the P. boryanum cyanobacterium. A method was selected and tested for the introduction of the vector into host cells. The needed orientation of pSM1 cyanobacterium plasmid within the vector as well as a possible role of its separate elements in inheriting the construction by host were defined.

Ampicillin↗

PubMed2005

Life-table analysis of Anopheles malaria vectors: generational mortality as tool in mosquito vector abundance and control studies.

BACKGROUND & OBJECTIVES: Vector control will for sometime remain a primary weapon in the war against vector borne diseases. Malaria is of paramount importance in this with its associated high morbidity and mortality especially in sub-Saharan Africa. This study on generational mortality associated factors in Anopheles mosquitoes life-table analysis was designed to investigate the fecundity, levels of mortality and mortality associated factors at the aquatic stages of anopheline malaria vectors. METHODS: Mortality associated factors were investigated at the eggs, I and II instar larval, III and IV instar larval and pupal stages of two anopheline species--Anopheles pseudopunctipennis (Theobald) and An. gambiae life-cycles in screen cages. Adult male and female mosquitoes were membrane filter-fed and algae in culture medium formed the bulk of food substances for the larval stage. Environmental temperature of culture media, pH and some associated physio-chemical factors were also determined. RESULTS: Results showed significant mortality rates at various aquatic stages. Infertility, cannibalism and environmental factors were the major factors responsible for mortality at the egg, larval and pupal stages respectively. INTERPRETATION & CONCLUSION: The aquatic stages of Anopheles mosquito mortality factor K and the mortality factors at the various stages investigated k1, k2, k3 and k4 are discussed. Our recommendations include further studies on the possible genetic modification of predacious An. pseudopunctipennis larvae and/or its modification for the production of sterile/infertile eggs as possible alternatives in the reduction and control of anopheline malaria burden.

Animals↗

PubMedDate not supplied

[Viral vectors in gene therapy. Advantages of the adenoassociated vectors].

Gene therapy has evolved due to the development of a number of biotechnology weapons, i.e., vectors that achieve for a longer expression and safer administration. Among viral vectors developed adeno-associated virus have shown promising advantages. These DNA viruses transduce a wide cell range, can integrate in host's genome and achieve for a long-period expression, besides avoiding a cellular immune response. The new technologies applied to the production and purification of these vectors had resulted in notable increases in quantity and quality of the infectious particles obtained. Actually, due to biotechnological advances, gene therapy is a potential therapeutic option.

Adenoviridae↗

PubMed1995

The constitutive expression of the immunomodulatory gp19k protein in E1-, E3- adenoviral vectors strongly reduces the host cytotoxic T cell response against the vector.

The immune response against cells infected by gene therapy vectors may be a major hindrance for gene therapy, destroying infected cells thus limiting the length of exogene expression and quickly eliminating infected cells on repeat administration. Adenoviruses and many other pathogens have evolved strategies for escape from immune surveillance, including the gp19k gene, found in the adenovirus E3 region, known to down-regulate major histocompatibility complex class 1 expression on the cell surface, and thus reduce lysis of the infected cells by cytotoxic T cells. We have constructed an adenoviral vector expressing the genes for beta-galactosidase and gp19k both under the control of constitutive promoters, and compared the capacity of lymphocytes from DBA/2 mice previously injected with the virus or with Ad-beta gal, a virus expressing beta-galactosidase but not gp19k, to lyse target cells infected with various viruses. Lymphocytes raised against Ad-beta gal fail to lyse target cells infected with Ad-beta gal-gp19k significantly, whereas Ad-beta gal infected target cells and a beta-galactosidase expressing cell line are strongly lysed. The administration of Ad-beta gal-gp19k fails to stimulate the proliferation of anti-vector lymphocytes, and thus these lymphocytes show poor cytotoxic activity against Ad-beta gal or Ad-beta gal-gp19k infected cells.

3T3 Cells↗

PubMed2004

Prediction of the bonding states of cysteines using the support vector machines based on multiple feature vectors and cysteine state sequences.

The support vector machine (SVM) method is used to predict the bonding states of cysteines. Besides using local descriptors such as the local sequences, we include global information, such as amino acid compositions and the patterns of the states of cysteines (bonded or nonbonded), or cysteine state sequences, of the proteins. We found that SVM based on local sequences or global amino acid compositions yielded similar prediction accuracies for the data set comprising 4136 cysteine-containing segments extracted from 969 nonhomologous proteins. However, the SVM method based on multiple feature vectors (combining local sequences and global amino acid compositions) significantly improves the prediction accuracy, from 80% to 86%. If coupled with cysteine state sequences, SVM based on multiple feature vectors yields 90% in overall prediction accuracy and a 0.77 Matthews correlation coefficient, around 10% and 22% higher than the corresponding values obtained by SVM based on local sequence information.

Amino Acids↗

PubMed2006

Proteometric study of ghrelin receptor function variations upon mutations using amino acid sequence autocorrelation vectors and genetic algorithm-based least square support vector machines.

Functional variations on the human ghrelin receptor upon mutations have been associated with a syndrome of short stature and obesity, of which the obesity appears to develop around puberty. In this work, we reported a proteometrics analysis of the constitutive and ghrelin-induced activities of wild-type and mutant ghrelin receptors using amino acid sequence autocorrelation (AASA) approach for protein structural information encoding. AASA vectors were calculated by measuring the autocorrelations at sequence lags ranging from 1 to 15 on the protein primary structure of 48 amino acid/residue properties selected from the AAindex database. Genetic algorithm-based multilinear regression analysis (GA-MRA) and genetic algorithm-based least square support vector machines (GA-LSSVM) were used for building linear and non-linear models of the receptor activity. A genetic optimized radial basis function (RBF) kernel yielded the optimum GA-LSSVM models describing 88% and 95% of the cross-validation variance for the constitutive and ghrelin-induced activities, respectively. AASA vectors in the optimum models mainly appeared weighted by hydrophobicity-related properties. However, differently to the constitutive activity, the ghrelin-induced activity was also highly dependent of the steric features of the receptor.

Algorithms↗

PubMed1994

Normal vector magnetocardiogram. I. Correlation with the normal vector ECG.

The vector magnetocardiogram (VMCG) has been measured with the corrected unipositional VMCG lead system and analyzed statistically in 290 normal subjects. The morphologic study of the QRS waveforms showed that in the right-to-left (X) component, the triphasic qRs waveform appeared in 55% of the subjects. The superoinferior (Y) component was characterized by a prominent S wave in 96% of the subjects, and the anteroposterior (Z) component was also characterized by a prominent S wave in 95% . The VMGs were compared with the vector electrocardiograms (VECG) recorded in a subgroup of 200 subjects, in whom both the VMCG and VECG were available for computer analysis. The normal variability of the spatial vector magnitude measurements was significantly greater in the VMCG than in the VECG. Some similarities were observed in the waveforms of the time-averaged QRS complexes between the VMCG and VECG. Multiple linear regression analysis between the VMCG and VECG showed that maximally 27, 45, and 41% of the variation in the instantaneous QRS X, Y, and Z amplitudes of the VMCG, respectively, could be explained by the instantaneous X, Y, and Z amplitudes of the VECG.

Adolescent↗

PubMed2006

Observation of spatially coherent polarization vector fields and visualization of vector singularities.

We present experimental observations of polarization vector fields from a highly isotropic microchip laser with a large Fresnel number. The experimental polarization vector field leads to complex entanglement of spatial structures and polarization states. We theoretically derive the representation of generalized coherent states to reconstruct the experimental polarization-resolved patterns. The analytical and precise reconstruction enables the vector singularities to be clearly visualized.

Journal Article↗

PubMed2002

Intravitreal injection of adeno-associated viral vectors results in the transduction of different types of retinal neurons in neonatal and adult rats: a comparison with lentiviral vectors.

Replication-deficient viral vectors encoding the marker gene green fluorescent protein (GFP) were injected into the vitreous of newborn, juvenile (P14), and adult rats. We tested two different types of modified virus: adeno-associated viral-2-GFP (AAV-GFP) and lentiviral-GFP vectors (LV-GFP). The extent of retinal cell transduction in different-aged animals was compared 7, 21, and 70 days after eye injections. At all postinjection times, LV-GFP transduction was mostly limited to pigment epithelium and cells in sclera and choroid. In contrast, transduction of large numbers of neural retinal cells was seen 21 and 70 days after AAV-GFP injections. AAV-GFP predominantly transduced neurons, although GFP-positive Müller cells were seen. All neuronal classes were labeled, but the extent of transduction for a given class varied depending on injection age. After P0 injections about 50% of transduced cells were photoreceptors and 30-40% were amacrine or bipolar cells. After adult injections 60-70% of transduced cells were retinal ganglion cells. In adults many GFP-positive retinal axons were traced through the optic nerve/tract and terminal arbors were visualized in central targets.

Adenoviridae↗

PubMed2002

Efficacy of gene therapy for a prototypical lysosomal storage disease (GSD-II) is critically dependent on vector dose, transgene promoter, and the tissues targeted for vector transduction.

Lysosomal storage diseases are an intriguing target for gene therapy approaches, as transduction of a "depot" organ with a transgene encoding a lysosomal enzyme can be followed by secretion, systemic distribution, downstream uptake, and lysosomal targeting of the enzyme into non-transduced tissues. These benefits are of utmost importance when considering gene therapy approaches for glycogen storage disease type-II (GSD-II). GSD-II is a prototypical lysosomal storage disorder caused by lack of intralysosomal acid alpha-glucosidase (GAA) activity. Lack of GAA can result in a proximal limb myopathy and respiratory and cardiac failure, each due to abnormal glycogen accumulation in the skeletal muscles or cardiac tissues, respectively. After converting the liver into a "depot" organ, we found that intravenous injection of the [E1-,polymerase-]AdGAA vector allowed for hepatic secretion of GAA over an at least 20-fold dosage range. We noted that very low plasma GAA levels (derived from hepatic secretion of GAA) can allow for GAA uptake by muscle tissues (skeletal or cardiac), but significantly higher plasma GAA levels are required before glycogen "cross-correction" can occur in these same tissues. We also demonstrated that liver-specific enhancer/promoters prolonged GAA transgene expression from persistent [E1-,polymerase-] adenovirus based vector genomes for at least 180 days, and significantly diminished the amounts of neutralizing anti-GAA antibodies elicited in this animal model. Finally, we demonstrated that skeletal muscles can also serve as a "depot" organ for GAA secretion, allowing for secretion of GAA and its uptake by noninfected distal tissues, although glycogen reductions in non-injected muscles were not achieved by the latter approach.

Adenoviridae↗

PubMedDate not supplied

Approaches to vector control: new and trusted. 4. Appropriate technology for vector control: impregnated bed nets, polystyrene beads and fly traps.

There are social, economic and entomological problems with conventional insecticidal spraying methods for vector control. There is therefore interest in alternative technologies, especially the impregnation of bed nets with pyrethroid insecticides against malaria vectors. This method is cheap, socially acceptable and effective where bed nets are already widely used and where malaria transmission is not very intense. In holoendemic areas, and where people consider bed nets unaffordable, there are still unanswered questions. Whether pyrethroid resistance will be selected in anophelines also deserves more attention than it has so far attracted. Where Culex mosquitoes breed in confined sites such as pit latrines, the application of floating layers of polystyrene beads is a long-lasting and effective control method. There is increasing evidence that house flies are important agents in the mechanical transmission of diarrhoea due to Shigella. Simple fly traps can be an effective way of controlling house fly populations and this deserves comprehensive testing in tropical countries.

Animals↗

PubMed1985

Improved M13 phage cloning vectors and host strains: nucleotide sequences of the M13mp18 and pUC19 vectors.

Three kinds of improvements have been introduced into the M13-based cloning systems. (1) New Escherichia coli host strains have been constructed for the E. coli bacteriophage M13 and the high-copy-number pUC-plasmid cloning vectors. Mutations introduced into these strains improve cloning of unmodified DNA and of repetitive sequences. A new suppressorless strain facilitates the cloning of selected recombinants. (2) The complete nucleotide sequences of the M13mp and pUC vectors have been compiled from a number of sources, including the sequencing of selected segments. The M13mp18 sequence is revised to include the G-to-T substitution in its gene II at position 6 125 bp (in M13) or 6967 bp in M13mp18. (3) M13 clones suitable for sequencing have been obtained by a new method of generating unidirectional progressive deletions from the polycloning site using exonucleases HI and VII.

Base Sequence↗