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PubMed2000

Critical aspects of viral vectors for gene transfer into the kidney.

Viral vectors have been used in vitro and in vivo for more than a decade, with some significant results in specific situations, e.g., when recombinant adeno-associated virus is used for the long-term transduction of skeletal muscle in coagulation factor IX-deficient patients. However, the kidney has been quite difficult to transduce with any viral vector currently available. When viral transduction occurs, it is often heterogeneous, transient, and eventually associated with immune and toxic side effects. However, recombinant adeno-associated virus and lentiviral vectors remain to be fully evaluated in the kidney; the former is small enough to be filtered through the glomerular basement membrane. This may be critical, because glomerular filtration is required for DNA complex-mediated transduction of tubular cells. An alternative to in situ renal gene transfer is secretion of a therapeutic protein from a distant site, such as skeletal muscle. Several examples provide evidence that this could be a clinically relevant approach. It also may allow accurate determination of the pathophysiologic mechanisms involved in the establishment and maintenance of experimental glomerulonephritis.

Animals↗
PubMed2002

[Development of gene-viral vector and its anti-tumor effect, a primary study].

OBJECTIVE: To develop a new kind of vector system, named as gene-viral vector, which combines the advantages of the gene therapy and virus therapy. METHOD: An anti-tumor gene was inserted into the genome of the replicative virus specific for the tumor cells by virus recombination technology. The killing effect, report gene expression of the green fluorescence protein, expression of the anti-tumor gene of mouse IL12, and the replication of the virus were observed respectively by cell pathology, fluorescence microscopy, ELISA and electron microscopy. RESULTS: A new kind of gene-viral vector system, in which the E1b-55 000 gene is deleted but the E1a gene of adenovirus is preserved, was constructed. The vector system possessed the same characteristics as the replicative virus ONYX-015, replication and proliferation in the tumor cells but not in the normal cells, thus specifically killing the tumor cells. Besides, it carried many kinds of anti-tumor genes. When carrying the report gene of the green fluorescence protein it made the expression of this gene in tumor cells far more effectively than the adenovirus vector employed in the traditional gene therapy did. However in the normal cells the expression of green fluorescence protein caused by this vector system was as little as or even less than that by the traditional adenovirus system. The similar result was also observed in the experiments of this vector system carrying the anti-tumor gene, gene of mouse IL12. The replication and proliferation of the virus carrying the gene of mouse IL12 in the tumor cells were confirmed by electron microscopy. CONCLUSION: Gene-viral vector is a new kind of vector in which the anti-tumor gene is inserted into the genome of the replicative virus specific for the tumor cells. It increases the expression of the anti-tumor gene by hundreds even tens of thousand times. It posseses all the advantages of gene therapy and virus therapy, thus further enhancing the curative effect and it overcomes such disadvantages as low transfer rate, low expression, lack of target tropism and low anti-tumor activity. It will become one of the most promising means in tumor treatment.

Adenoviridae↗
PubMed2005

Synthetic, self-assembly ABCD nanoparticles; a structural paradigm for viable synthetic non-viral vectors.

Gene therapy research is still in trouble owing to a paucity of acceptable vector systems to deliver nucleic acids to patients for therapy. Viral vectors are efficient but may be too dangerous. Synthetic non-viral vectors are inherently safer but are currently not efficient enough to be clinically viable. The solution for gene therapy lies with improved synthetic non-viral vectors systems. This review is focused on synthetic cationic liposome/micelle-based non-viral vector systems and is a critical review written to illustrate the increasing importance of chemistry in gene therapy research. This review should be of primary interest to synthetic chemists and biomedical researchers keen to appreciate emerging technologies, but also to biological scientists who remain to be convinced about the relevance of chemistry to biology.

Cations↗
PubMed2006

Gene therapy for transplantation with viral vectors--how much of the promise has been realised?

Gene therapy holds promise in preventing the development of many diseases. One of the possible applications is the management of organ transplantation. Over the years, advances in vector development have allowed the clinical progression of this form of therapy to become more attainable. Viral vector technology has proved to be better than non-viral vectors at ferrying therapeutic genes to cells. However, many deficiencies in viral vectors hinder the full realisation of gene-based therapy in transplantation. Here, these deficiencies and their ramifications for the future of viral vector development are fully analysed. The authors propose that the slow progress of gene therapy in transplantation may be related to the deficiencies in viral vectors.

Apoptosis↗
PubMed1997

Defective viral vectors as agents for gene transfer in the nervous system.

Viral vectors have attracted great interest as vehicles for gene therapy. Due to concerns regarding continued viral gene expression in several systems, new approaches have been sought for gene transfer in the nervous system. This article reviews the general concepts and basic biology of defective viral vectors. These are vectors which can package into a viral coat but contain no viral genes, thereby allowing efficient gene transfer in the absence of viral gene expression in target cells. The defective herpes simplex virus (HSV) vector has been applied to numerous interesting questions in neurobiology. The inability to completely eliminate helper viruses has raised concern regarding the application of this vector to human disease. The adeno-associated virus (AAV) vector has recently been introduced into the nervous system. This vector harbors no viral genes, however helper viruses can also be completely eliminated from the system. Although the smaller size may limit the range of applications for this vector, it has received great interest as a potential agent for gene therapy in the nervous system. Potential future directions are discussed as well.

Animals↗
PubMed2003

Ultrasound enhances the transfection of plasmid DNA by non-viral vectors.

Increasing attention has been paid to technology used for the delivery of genetic materials into cells for gene therapy and the generation of genetically engineered cells. So far, viral vectors have been mainly used because of their inherently high transfection efficiency of gene. However, there are some problems to be resolved for the clinical applications, such as the pathogenicity and immunogenicity of viral vectors themselves. Therefore, many research trials with non-viral vectors have been performed to enhance their efficiency to a level comparable to the viral vector. Two directions of these trials exist: material improvement of non-viral vectors and their combination with various external physical stimuli. This paper reviews the latter research trials, with special attention paid to the enhancement of gene expression by ultrasound (US). The expression level of plasmid DNA by various cationized polymers and liposomes is promoted by US irradiation in vitro as well as in vivo. This US-enhanced expression of plasmid DNA will be discussed to emphasize the technical feasibility of US in gene therapy and biotechnology.

Animals↗
PubMed2000

Viral vectors for gene delivery and gene therapy within the endocrine system.

The transfer of genetic material into endocrine cells and tissues, both in vitro and in vivo, has been identified as critical for the study of endocrine mechanisms and the future treatment of endocrine disorders. Classical methods of gene transfer, such as transfection, are inefficient and limited mainly to delivery into actively proliferating cells in vitro. The development of viral vector gene delivery systems is beginning to circumvent these initial setbacks. Several kinds of viruses, including retrovirus, adenovirus, adeno-associated virus, and herpes simplex virus, have been manipulated for use in gene transfer and gene therapy applications. As different viral vector systems have their own unique advantages and disadvantages, they each have applications for which they are best suited. This review will discuss viral vector systems that have been used for gene transfer into the endocrine system, and recent developments in viral vector technology that may improve their use for endocrine applications - chimeric vectors, viral vector targeting and transcriptional regulation of transgene expression.

Endocrine System↗
PubMed2001

Induction of adult-like antibody, Th1, and CTL responses to measles hemagglutinin by early life murine immunization with an attenuated vaccinia-derived NYVAC(K1L) viral vector.

Although initially developed in adult animals, novel viral vectors expressing recombinant measles antigens must eventually prove their success in the early life setting, where the efficacy of the currently used live-attenuated measles virus vaccine is limited. The immunological requirements for vaccine candidates include the generation of protective antibody responses as well as the induction of Th1 and cytotoxic T lymphocytes (CTL) responses, which is challenging in the neonatal setting. Here, we report that young BALB/c mice immunized with a single dose of a vaccinia-based NYVAC(K1L) vector generate adult-like antihemagglutinin (HA) antibody responses as well as adult-like Th1 and CTL responses. Despite this strong immunogenicity in early life, antibody responses (but not T-cell responses) to a single dose of NYVAC(K1L)-HA remained susceptible to inhibition by preexisting measles antibodies, calling for use of prime-boost strategies. NYVAC(K1L)-HA is the first attenuated live viral vector demonstrated as capable of inducing adult-like antibody, Th1, and CTL responses against measles in an early life murine immunization model, a capacity previously only reported for measles DNA vaccines.

Animals↗
PubMed2003

Latest development in viral vectors for gene therapy.

Gene therapy includes the application of various viral vectors, which represent most types and families of viruses, suitable for infection of mammalian host cells. Both hereditary diseases and acquired illnesses, such as cancer, can be targeted. Because of the various properties of each viral vector, the definition of their application range depends on factors such as packaging capacity, host range, cell- or tissue-specific targeting, replication competency, genome integration and duration of transgene expression. Recent engineering of modified viral vectors has contributed to improved gene delivery efficacy.

Adenoviridae↗
PubMed1995

Gene expression from recombinant viral vectors in the central nervous system after blood-brain barrier disruption.

Direct intracerebral injection of recombinant adenoviral vectors within the brain parenchyma or the ventricular system results in a limited volume of distribution of virus, as demonstrated by transgene expression. Global delivery to the central nervous system may increase the use of these vectors but only if the viral vectors can cross the blood-brain barrier and result in transduction of the underlying cells. This short-term study examines whether osmotic disruption with mannitol can result in sufficient opening of the vascular endothelium to allow for passage of replication-defective adenovirus containing the Escherichia coli beta-galactosidase gene (lacZ). Virus was injected into the carotid artery of rats after blood-brain barrier disruption with intracarotid hypertonic mannitol, and the animals were killed and analyzed after 4 days. Histochemical analysis and electron microscopy confirmed expression of the E. coli lacZ gene in the pericapillary astrocytes of the ipsilateral cerebral cortex and deep grey matter. Furthermore, the extent of gene transfer and expression correlated with the degree of barrier opening, as measured by Evans blue staining. Transgene expression was not seen in control animals that received intracarotid saline before recombinant virus injection. These data demonstrate, for the first time, that blood-brain barrier disruption can allow for the delivery of functional viral vectors to the central nervous system.

Adenoviridae↗
PubMed2006

From leading role to the backstage: mesenchymal stem cells as packaging cell lines for in situ production of viral vectors.

Gene therapy is based on the genetic manipulation of target cells. The genetic information required to genetically engineer these cells can be delivered through non-viral or viral vectors that present different biologic properties. The production of viral vectors for gene therapy depends on the nature of the cells transfected with plasmids containing the genetic information for recombinant viral assemblage. These so-called packaging cell lines (PCL) can be injected into the target organ, for the in situ transduction of target cells. There have been recent reports about the capacity of mesenchymal stem cells (MSCs) to target tumor cells. Different research groups, including our own, have isolated these MSCs, but they have not yet been studied as potential PCL to produce viral vectors. We propose here that a MSC packaging cell line could be employed for in situ gene therapy of solid tumors. The tropism of MSCs for tumor cells may render this PCL more efficient in that microenvironment, producing viral vectors for longer periods of time, shifting MSCs from target cell to the backstage level of viral gene therapy.

Adenoviridae↗
PubMed2002

Adeno-associated viral vectors as agents for gene delivery: application in disorders and trauma of the central nervous system.

The use of viral vectors as agents for gene delivery provides a direct approach to manipulate gene expression in the mammalian central nervous system (CNS). The present article describes in detail the methodology for the injection of viral vectors, in particular adeno-associated virus (AAV) vectors, into the adult rat brain and spinal cord to obtain reproducible and successful transduction of neural tissue. Surgical and injection procedures are based on the extensive experience of our laboratory to deliver viral vectors to the adult rat CNS and have been optimized over the years. First, a brief overview is presented on the use and potential of viral vectors to treat neurological disorders or trauma of the CNS. Next, methods to deliver AAV vectors to the rat brain and spinal cord are described in great detail with the intent of providing a practical guide to potential users. Finally, some data on the experimental outcomes following AAV vector-mediated gene transfer to the adult rat CNS are presented as is a brief discussion on both the advantages and limitations of AAV vectors as tools for somatic gene transfer.

Adenoviridae↗
PubMed2006

New viral vector for efficient production of target proteins in plants.

A new potato virus X (PVX)-based viral vector for superproduction of target proteins in plants has been constructed. The triple gene block and coat protein gene of PVX were substituted by green fluorescent protein. This reduced viral vector was delivered into plant cells by agroinjection (injection of Agrobacterium tumefaciens cells, carrying viral vector cDNA within T-DNA, into plant leaves), and this approach allowed to dramatically reduce the size of the vector genome. The novel vector can be used for production of different proteins including pharmaceuticals in plants.

Agrobacterium tumefaciens↗
PubMed2002

Adeno-associated viral vectors penetrate human solid tumor tissue in vivo more effectively than adenoviral vectors.

The transduction efficiencies of adeno-associated viral vectors (AAV, serotype 2) and adenovirus vectors (ADV, serotype 5) were examined in three different models of cancer. First, we used flow cytometry to quantitate AAV-GFP or ADV-GFP transduction in 13 cell lines derived from malignant tissue (6 gliomas, 6 mammary cancers, and 1 leukemia). These experiments showed variable transduction efficiency (0%-81%) between the cell lines, with ADV being more effective compared to AAV in 9 of 13 cell lines. Second, spheroids prepared from human glioblastomas were infected with ADV or AAV expressing GFP or lacZ cassettes, and after 2 weeks, uniform reporter gene expression was observed on the spheroid. Whereas AAV produced consistent transduction throughout the spheroids, ADV infection was mainly limited to the outer cell layers of the spheroids, suggesting that AAV were more efficient at penetrating solid tumor tissue. Third, human biopsies from glioblastoma multiforme patients were xenografted into nude rats and grown for 4 weeks followed by viral vector injection. Combined use of high-resolution magnetic resonance imaging (MRI) and histologic analysis allowed the identification of transduced cells and their spatial distribution within the tumors. AAV-mediated transgene expression was observed in cell clusters through the entire tumor, while ADV-mediated transduction was restricted to cells at the tumor periphery. Thus, while AAV and ADV vectors may infect tumor-derived cell lines to a similar degree, AAV penetrated glioblastoma spheroids and xenografts more efficiently compared to ADV vectors. These results suggest that AAV may be suitable for therapeutic gene delivery to malignant tumors.

Adenoviridae↗
PubMed2003

Comparison of viral vectors: gene transfer efficiency and tissue specificity in a bladder cancer model.

PURPOSE: Gene transfer efficiency and specific cell targeting of vectors is a major obstacle in preclinical studies of gene therapy for malignant disease. Previous attempts at gene transfer in bladder cancer models have resulted in variable urothelial and tumor transgene expression after intravesical administration of recombinant viral vectors. In the current study we compared the gene transfer efficiencies of different viral vectors. MATERIALS AND METHODS: We compared the gene transfer efficiencies of the viral vectors replication-deficient adenovirus, attenuated vaccinia virus (NYVAC) and canarypox virus (ALVAC) in vitro and in an orthotopic murine bladder cancer model. We used beta-galactosidase and firefly luciferase reporter gene expression to compare gene transfer efficiency. RESULTS: Significantly higher transgene expression was observed in vitro when these cells were infected with NYVAC or ALVAC compared with adenovirus vectors. Similarly the efficiency of adenovirus vectors to transfer genetic material into bladder urothelium and orthotopic bladder tumors was inferior to that of ALVAC and NYVAC vectors, which interestingly appeared to have a predilection to infect the orthotopic tumor. Analysis of the expression of coxsackie-adenovirus receptor using reverse transcriptase-polymerase chain reaction revealed the bladder tumor cell lines were lacking this adenovirus receptor. While adenovirus transferred genes poorly to normal bladder, coxsackie-adenovirus receptor expression was high in bladder tissue. CONCLUSIONS: The viral vectors examined in these experiments resulted in significantly different gene transfer in the orthotopic bladder cancer model, underscoring the importance of vector selection in gene therapy protocols.

Adenoviridae↗
PubMed2005

Remote nerve injection of mu opioid receptor adeno-associated viral vector increases antinociception of intrathecal morphine.

UNLABELLED: We have shown previously that using recombinant adeno-associated viral vector (rAAV) to up-regulate mu opioid receptors (muORs) in dorsal root ganglia (DRGs) increases the potency of subcutaneous morphine. Here we report an improved method of introducing rAAV-muOR viral vectors into DRGs. Instead of injecting the rAAV-muOR gene directly into DRGs as shown before, the vector was introduced into the sciatic nerve of rats. Changes in muOR expression and antinociceptive effects of intrathecal morphine in rAAV-muOR rats were examined. Immunocytochemical studies showed that the transduced muORs were expressed in all types (ie, small, medium, and large) of DRG neurons. The expression of muORs in DRG neurons, quantified by Western blotting, was increased by 1.7-fold 4 weeks after the sciatic nerve injection. The up-regulation persisted for more than 6 months. The effects of intrathecal morphine on paw withdrawal latencies to heat were studied in rats inflamed with complete Freund's adjuvant. Compared with rats injected with rAAV containing the enhanced green fluorescent protein gene (rAAV-EGFP), the antinociceptive potency of intrathecal morphine in rAAV-muOR rats was significantly increased, and the effective dose (ED50) for morphine was 5.4-fold lower (rAAV-muOR: ED50 = 0.84 microg, confidence interval, 0.70-0.99 microg; rAAV-EGFP: ED50 = 4.50 microg, confidence interval, 3.55-5.86 microg). With minimum tissue damage and a large persistent increase in the opioid potency, remote nerve injection of rAAV-muOR to up-regulate muORs could be a useful therapeutic strategy for the treatment of chronic pain. PERSPECTIVE: Injection of adeno-associated viral vector containing the muOR gene into the sciatic nerve produces a significant up-regulation of muORs in DRGs for up to 6 months without producing any immune responses in the injected animals. This results in a 5.4-fold increase in the potency of intrathecal morphine.

Analgesics, Opioid↗
PubMed2001

Viral vectors for dendritic cell-based immunotherapy.

Transduction of dendritic cells (DCs) by viral vectors genetically engineered to express tumor-associated antigens (TAAs) or cytokines can produce a high level of transgene expression and is an attractive approach for DC-based immunotherapy. Ex vivo transduction allows the control of DC quality, antigen quantity and site of DC reinjection. This review evaluates the viral vectors currently being developed for use in DC-based immunotherapy.

Adjuvants, Immunologic↗
PubMed2006

Delivery of viral vectors to tumor cells: extracellular transport, systemic distribution, and strategies for improvement.

It is a challenge to deliver therapeutic genes to tumor cells using viral vectors because (i) the size of these vectors are close to or larger than the space between fibers in extracellular matrix and (ii) viral proteins are potentially toxic in normal tissues. In general, gene delivery is hindered by various physiological barriers to virus transport from the site of injection to the nucleus of tumor cells and is limited by normal tissue tolerance of toxicity determined by local concentrations of transgene products and viral proteins. To illustrate the obstacles encountered in the delivery and yet limit the scope of discussion, this review focuses only on extracellular transport in solid tumors and distribution of viral vectors in normal organs after they are injected intravenously or intratumorally. This review also discusses current strategies for improving intratumoral transport and specificity of viral vectors.

Animals↗