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At least 19 recordsLinked to original sources

PubMed2002

Engineering the surface properties of synthetic gene delivery vectors.

Synthetic gene delivery vehicles are a highly promising approach to gene delivery; however, several problems must still be overcome before they can begin to enjoy dinical success. A number of these problems can be addressed by engineering and optimizing the properties of the vector surface, the component of the particle that interacts and "communicates" with tissues and cells during the delivery process. Surfaces must be engineered to satisfy two ostensibly conflicting constraints: the ability to interact specifically with a target cell while avoiding nonspecific protein interactions, particularly with components of the immune system. We summarize progress that has been made in both these areas and discuss several approaches where the intersection of biological and chemical solutions promises to significantly advance the engineering of synthetic vehicles.

Animals↗

PubMed2000

Targeted synthetic gene delivery vectors.

Synthetic gene delivery vehicles have made significant progress in the past decade in demonstrating strong potential for targeted delivery to specific cells, low toxicity and immunogenicity and large carrying capacity. However, significant advances must still be made to increase the efficiency of both polymer and lipid vehicles. Furthermore, techniques to generate more effective targeting moieties for a variety of cell types, as well as means to consistently assemble vectors containing these targeting ligands, are areas for further improvement. This review focuses on significant recent advances in generating a number of novel targeted vectors, and discusses progress in the development of new genetic and chemical systems to enhance the targeting, assembly and biocompatibility of synthetic vectors.

Animals↗

PubMed2004

Development of herpesvirus-based episomally maintained gene delivery vectors.

Successful gene therapy aims to deliver and express therapeutic genes to cure or slow the progression of disease. However, a major obstacle in the application of gene therapy has been the development of the vectors used to deliver heterologous DNA to the cell or tissue of choice. A number of viral- and non-viral-based vector systems have undergone clinical trials with varying success. However, at present, no vector system possesses the full complement of properties that are generally believed necessary in an ideal gene delivery system. Therefore, alongside attempts to improve current gene delivery vectors, the identification and evaluation of new viral vectors is crucial for the long-term success of gene therapy. Herpesviruses are large DNA viruses which possess a number of advantages as gene delivery vectors. These relate to an ability to package large DNA insertions and establish lifelong latent infections in which the genomic material exists as a stable episome. This review aims to highlight the potential of herpesvirus vectors, in particular an alternative vector system based on herpesvirus saimiri (HVS). HVS is capable of infecting a range of human cell lines with high efficiencies, and the viral genome persists as high copy number, circular, non-integrated episomes which segregate to progeny following cell division. This allows the virus-based vector to stably transduce a dividing cell population and provide sustained transgene expression for an extended period of time both in vitro and in vivo. Moreover, the insertion of a bacterial artificial chromosome cassette into the HVS genome simplifies the incorporation of large amounts of heterologous DNA for gene delivery. These properties offer characteristics similar to an artificial chromosome combined with an efficient delivery system and merit its continual development as a possible gene delivery vector for the future.

Gene Transfer Techniques↗

PubMedDate not supplied

Designing gene delivery vectors for cardiovascular gene therapy.

Genetic therapy in the cardiovascular system has been proposed for a variety of diseases ranging from prevention of vein graft failure to hypertension. Such diversity in pathogenesis requires the delivery of therapeutic genes to diverse cell types in vivo for varying lengths of time if efficient clinical therapies are to be developed. Data from extensive preclinical studies have been compiled and a certain areas have seen translation into large-scale clinical trials, with some encouraging reports. It is clear that progress within a number of disease areas is limited by a lack of suitable gene delivery vector systems through which to deliver therapeutic genes to the target site in an efficient, non-toxic manner. In general, currently available systems, including non-viral systems and viral vectors such as adenovirus (Ad) or adeno-associated virus (AAV), have a propensity to transduce non-vascular tissue with greater ease than vascular cells thereby limiting their application in cardiovascular disease. This problem has led to the development and testing of improved vector systems for cardiovascular gene delivery. Traditional viral and non-viral systems are being engineered to increase their efficiency of vascular cell transduction and diminish their affinity for other cell types through manipulation of vector:cell binding and the use of cell-selective promoters. It is envisaged that future use of such technology will substantially increase the efficacy of cardiovascular gene therapy.

Adenoviridae↗

PubMed1998

Viral and nonviral gene delivery vectors for cancer gene therapy.

The development of vectors that are capable of efficient gene delivery is crucial to the success of gene therapy. We have developed both recombinant viral and nonviral vectors with the goal of correcting genetic abnormalities in cancer cells that are responsible for malignant transformation. Infection of cancer cells by recombinant adenovirus (Adv) indicates that the level of transduction is variable and dependent on the virus-to-cell ratio. Infection of cells with Adv/p53 resulted in levels of tumor suppressor p53 gene expression that could mediate tumor cell growth suppression and apoptosis, both in vitro and in vivo. The treatment of cancer cells with cisplatin prior to Adv transduction resulted in a higher level of therapeutic gene expression. Epidermal growth factor (EGF)/DNA complexes targeted to cancer cells overexpressing the EGF receptor resulted in efficient transduction of several lung cancer cell lines in vitro. As a result, these vectors provide improved methods with which to treat cancer in the clinical setting with gene therapy.

Adenoviridae↗

PubMed2003

Herpesvirus saimiri: a potential gene delivery vector (review).

The success of human gene therapy relies on efficient delivery and appropriate expression of therapeutic genes which will cure or slow the progression of a disease. However, current viral vectors do not possess the full complement of properties that are generally believed necessary in an ideal gene delivery system. Therefore, alongside attempts to improve current gene delivery vectors, the identification and evaluation of new viral vectors is crucial to the long-term success of gene therapy. Herpesviruses are large DNA viruses which possess a number of advantages as gene delivery vectors. These relate to an ability to package large DNA insertions and establish lifelong latent infections in which the genomic material exists as a stable episome. This review aims to high-light an alternative herpesvirus vector system based on Herpesvirus saimiri (HVS), and illustrates the properties and development of this potential gene delivery vector. HVS is the prototype gamma-2 herpesvirus, or rhadinovirus, originally isolated from its natural host, the squirrel monkey. HVS is capable of infecting a range of human cell lines with high efficiencies, in particular human carcinoma cell lines. Moreover, the HVS viral genome does not integrate into the cellular genome and persist as a high copy number, circular, non-integrated episome which segregate to progeny upon cell division. This allows the virus to stably transduce a dividing cell population and provide sustained transgene expression for an extended period of time in both in vitro and in vivo studies. These properties merit its continual development as a possible gene delivery vector for the future.

Carcinoma↗

PubMed2002

Viruses as gene delivery vectors: application to gene function, target validation, and assay development.

A Biochemical Pharmacology Discussion Group Conference, was held at the headquarters of the New York Academy of Sciences on December 4, 2001 as part of an ongoing series designed to highlight and review areas important to modern drug development (Figure 1). Briefly introduced by Tom Kost (GlaxoSmithKline) and Michael Lotze (University of Pittsburgh), the focus was on the intersection of genomics, proteomics, and now "viromics." The latter term refers to the use of viruses and viral gene transfer to explore the complexity arising from the vast array of new targets available from the human and murine genomes. Indeed, access to large numbers of genes using viral vectors is a key tool for drug discovery and drug delivery. With 38,000 genes identified within the human genome, only 5000 are considered readily druggable. Generating tools such as these to validate targets represents a major part of the armamentarium of the postgenomic scientist. During the last 12 years alone, there have been over 26,000 publications on virus vectors. Many of them have been found useful in target validation, assay development, and evaluation in in vivo models and gene therapy. Thus, there is now an extensive knowledge base for several viral vectors, with unique attributes within each of them providing versatility, efficiency, and ease of use. The individual scientists presenting at the meeting illustrated many of the unique and useful characteristics of such vector systems including retrovirus, adenovirus, herpes virus, simbis virus, and baculovirus.

Animals↗

PubMed2005

Recombinant polymers for cancer gene therapy: a minireview.

A major challenge for successful cancer gene therapy is the development of safe and effective gene delivery vectors. Gene delivery vectors can be viral or nonviral. Among nonviral vectors various polymeric vectors have shown potential in gene delivery. However, much work needs to be done in order to correlate polymer structure with gene release at the target site and transfection efficiency. This article is a brief introduction into cancer gene therapy, barriers and methods for gene transfer with emphasis on the applications of recombinant polymers for cancer gene therapy.

Amino Acid Sequence↗

PubMed2004

Cell-selective viral gene delivery vectors for the vasculature.

Clinical gene therapy for cardiovascular disease remains achievable. To date, however, preclinical studies and clinical trials have highlighted shortfalls in viral gene delivery to vascular cells. These include poor efficiency, poor target tissue selectivity, the presence of pre-existing neutralizing antibodies and immunogenicity generated by the host to vectors such as adenovirus. These important issues require careful consideration when applying viral vectors for gene therapy. Each delivery vector requires precise optimization and tailoring for each disease application since parameters relating to vector : tissue exposure time, route of delivery and target cell type vary considerably. Optimization can be achieved through modification of the structure of the virus capsid proteins and expression cassette to generate vectors that are highly selective and efficient for target cell binding and entry as well as instilling transcriptional control and/or longevity on transgene expression. This ultimately will improve the efficacy and toxicity profiles of gene delivery vectors and has become a very important area in gene therapy. Here, we review recent advances in the targeting of viral gene delivery vectors to the vasculature.

Adenoviridae↗

PubMed2006

Herpesvirus saimiri-based gene delivery vectors.

Herpesviruses possess a number of characteristics which make them promising gene delivery vectors. These include their capacity to package large amounts of heterologous DNA and an ability to establish persistent, lifelong infections, where the viral genome remains as a circular non-integrated episome. Herpesvirus saimiri (HVS) is the prototype gamma-2 herpesvirus and is currently being developed as a potential gene delivery vector. In addition to the above properties, HVS-based vectors have the ability to infect a wide range of human cell lines and primary cultures with high efficiencies. Moreover, upon infection the viral genome persists as high copy number, circular, non-integrated episomes which segregate to progeny cells upon division. This allows the HVS-based vector to stably transduce a dividing cell population and provide sustained heterologous gene expression. As such, it offers the characteristics of an artificial chromosome combined with a highly efficient delivery system. This review aims to describe the assessment of HVS-based vectors in both in vitro and in vivo studies, highlighting new developments and possible applications for the treatment of genetic diseases.

Animals↗

PubMed2001

Quantitative analysis of synthetic gene delivery vector design properties.

As intracellular gene delivery pathways are highly complex combinations of multiple potentially rate-limiting cellular and molecular processes, approaches to the design of synthetic delivery vectors focusing on any single barrier individually will likely be suboptimal. We offer here an "integrative systems" approach to vector characterization and design, combining quantitative experiment and computational modeling studies of vector uptake and trafficking kinetics. This model is validated using data for delivery of a green fluorescent protein (GFP)-encoding plasmid by means of Lipofectamine, permitting specification of model parameter values. The model is then used to make a priori predictions on the effect of polymer length in polyplex vectors, with additional parameter values determined from previous independent experimental studies of plasmid release. Comparison with data on GFP expression via these polyplex vectors shows that the model successfully predicts an experimentally observed biphasic dependence of expression efficiency on polymer length and quantifies the contributions of competing effects yielding the optimal intermediate polymer length. Finally, we use the model to predict potential effects of incorporating nuclear localization sequences in these kinds of synthetic vectors, and find that the degree of benefit from these will depend on the values of other key system properties including the vector unpackaging rate constant. Thus, we demonstrate the usefulness of a bioengineering, integrative-systems modeling approach to improved vector design and analysis.

Biological Transport↗

PubMed2002

On the kinetics of polyplex endocytic trafficking: implications for gene delivery vector design.

Synthetic gene therapy vectors must be designed to safely and efficiently escort DNA from outside the cell to the nucleus and to overcome several physical barriers that are obstacles to internalization, escape from endocytic vesicles, movement through the cytoplasm, and transport into the nucleus. By providing a firm foundation for polymer design, a quantitative understanding of polymer-mediated gene delivery mechanisms may allow more efficient and timely design of new vectors. We have used a flow-cytometry-based assay for investigating endocytic trafficking by quantitation of polyplex pH microenvironments. We investigated polyethylenimine (PEI)- and poly-L-lysine (PLL)-DNA trafficking, with and without the endosomotropic agent chloroquine. PLL-DNA complexes appear to be localized to early endocytic vesicles and are not trafficked to lysosomes. Further, chloroquine appears to facilitate PLL-mediated gene delivery by a mechanism other than buffering of endocytic compartments. Additionally, PEI does not appear to buffer endocytic compartments, but requires exposure to an acidic environment for efficient gene delivery.

Fluorescent Dyes↗

PubMed2000

Cytokine production in motor neurons by poliovirus replicon vector gene delivery.

Poliovirus replicon vectors transiently express foreign proteins selectively in motor neurons of the anterior horn of the spinal cord. Here we intraspinally inoculated mice transgenic for the poliovirus receptor (PVR) with replicons encoding murine tumor necrosis factor alpha (mTNF-alpha). We detected high-level expression of mTNF-alpha in the spinal cords of these animals at 8-12 h post inoculation; this returned to background by 72 h. The mice exhibited ataxia and tail atony, whereas animals given a replicon encoding green fluorescent protein (GFP) exhibited no neurological symptoms. Histology of spinal cords from mice given the replicon encoding mTNF-alpha revealed neuronal chromatolysis, reactive astrogliosis, decreased expression of myelin basic protein, and demyelination. These animals recovered with only slight residual damage. This study shows that replicon vectors have potential for targeted delivery of therapeutic proteins to the central nervous system and provide a new approach for treatment of spinal cord trauma and neurological disease.

Animals↗

PubMed2006

Directed evolution of adeno-associated virus yields enhanced gene delivery vectors.

Adeno-associated viral vectors are highly safe and efficient gene delivery vehicles. However, numerous challenges in vector design remain, including neutralizing antibody responses, tissue transport and infection of resistant cell types. Changes must be made to the viral capsid to overcome these problems; however, very often insufficient information is available for rational design of improvements. We therefore applied a directed evolution approach involving the generation of large mutant capsid libraries and selection of adeno-associated virus (AAV) 2 variants with enhanced properties. High-throughput selection processes were designed to isolate mutants within the library with altered affinities for heparin or the ability to evade antibody neutralization and deliver genes more efficiently than wild-type capsid in the presence of anti-AAV serum. This approach, which can be extended to additional gene delivery challenges and serotypes, directs viral evolution to generate 'designer' gene delivery vectors with specified, enhanced properties.

Adenoviridae↗

PubMed2003

Stimuli-responsive gene delivery vectors.

One of the major limitations to efficient gene delivery mediated by synthetic non-viral vectors is the presence of various barriers between the site of administration and localization in the cell nucleus. Each of the barriers often demands significantly different properties from the vector. Delivery vectors that can recognize changes in the environment and that are capable of actively responding by altering their properties or behavior are therefore being developed to address the challenge of integrating the sometimes contradictory characteristics necessary for effective gene delivery. This review discusses recent developments in the area of gene delivery vectors capable of responding to various endogenous and exogenous stimuli by changing their properties or behavior.

Acoustic Stimulation↗

PubMed2005

Thermoresponsive polymers as gene delivery vectors: cell viability, DNA transport and transfection studies.

A range of gene delivery vectors containing the thermoresponsive polymer, poly(N-isopropylacrylamide) (PNIPAm) was evaluated for effects on cell viability, intracellular trafficking and transgene expression in C2C12 mouse muscle cells. Polymers were complexed with plasmid DNA at pH 7.4 and the ability of the resulting particles to transfect cells was assessed via confocal microscopy and protein expression studies in tissue culture. Cell viability assays indicated that these polymers were toxic at high concentrations when not complexed to DNA or at certain polymer:DNA ratios. Poly(ethyleneimine) co-polymers with side-chain grafted PNIPAm were shown to be less toxic than poly(ethyleneimine) alone or PNIPAm-co-(N,N'-dimethylaminoethylmethacrylate) linear co-polymers and the effects were concentration dependent. Confocal micrographs of labeled polymers and DNA indicated rapid cellular entry for all the complexes but expression of Green Fluorescent Protein was achieved only when the branched PEI-PNIPAm co-polymers were used as vectors. The results indicate that design of appropriate co-polymer components and overall polymer architecture can be used to mediate, and perhaps ultimately control, DNA transport and transgene expression.

Acrylic Resins↗

PubMed1995

Plasmid insertion vectors that facilitate construction of herpes simplex virus gene delivery vectors.

Plasmid insertion vectors were designed for the expression of foreign genes in recombinant herpes simplex virus (HSV) vectors. One vector, pGal9, was designed for the insertion of foreign genes with their own promoter; a second vector, pGal10, was designed for the insertion of coding sequences downstream from the HSV immediate-early 110K promoter. The 110K promoter directed efficient expression of foreign genes, particularly in replication-incompetent virus recombinants, as shown by the expression of the lacZ and IFN alpha genes. These vectors should be useful for the characterization of various promoters for gene delivery, and for the efficient expression of foreign genes in a variety of cell types.

Animals↗

PubMed2006

[Progress in research of chitosan as a non-viral gene delivery vector].

Efficiency of non-viral gene delivery based on chitosan and chitosan derivatives as DNA condensing carrier is dependent on a series of factors, such as complex size, the charge ratio of chitosan/DNA, molecular mass of chitosan, the degree of chitosan deacetylation, pH and serum concentration of the transfection medium. Through modifying the chitosan in a certain extent, we can change the efficiency of transfection. Studies on transfection condition, efficiency and mechanism using chitosan and chitosan derivatives as transfection agents are reviewed.

Animals↗