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At least 19 recordsLinked to original sources

PubMed2001

Homing markers for atherosclerosis: applications for drug delivery, gene delivery and vascular imaging.

Endothelial dysfunction plays a major role in the pathogenesis of atherosclerosis. Pro-inflammatory cytokines such as interleukin-1 beta and tumour necrosis factor alpha activate endothelial cells changing their resting phenotype to become pro-adhesive, pro-thrombotic and pro-atherogenic. Phage display in vivo biopanning has been used to identify peptide sequences that home to diseased regions of the vessel wall in low density lipoprotein receptor (LDLr) knockout mice. In LDLr knockout mice, peptide sequence determinants exhibiting organ specificity have been isolated. These sequences have applications for gene delivery, drug delivery and for improving contrast agents for vascular imaging.

Animals↗

PubMed2005

Recent advances in non-viral gene delivery.

Gene therapy has been deemed the medicine of the future due to its potential to treat many types of diseases. However, many obstacles remain before gene delivery is optimized to specific target cells. Over the last several decades, many approaches to gene delivery have been closely examined. By understanding the factors that determine the efficiency of gene uptake and expression as well as those that influence the toxicity of the vector, we are better able to develop new vector systems. This chapter will provide a brief overview of recent advances in gene delivery, specifically on the development of novel non-viral vectors. The following chapters will provide additional details regarding the evolution of non-viral gene delivery systems.

Cations↗

PubMed2005

Recent Advances in Non-viral Gene Delivery.

Journal Article↗

PubMed2004

Vaccinia as a vector for gene delivery.

Gene therapy is a promising approach, yet so far it has shown limited effectiveness in many clinical trials, mainly due to insufficient gene transduction. Recombinant vaccinia virus (rVV) has been well developed as a gene delivery vector, initially for protein expression in mammalian cells. rVV has been further developed to express antigens in vivo in generating immunity for protection against specific infectious diseases and cancer. rVVs, as non-replicating viral vectors, have been demonstrated for their great potential as vaccines, for their diminished cytopathic effects, high levels of protein expression and strong immunogenicity, and they are relatively safe in animals and in human patients. A number of clinical trials using rVVs as vaccines have shown promising results for treating infectious diseases and cancer. In the last few years, due to its exceptional ability to replicate in tumour cells, the Western Reserve strain vaccinia has been explored as a replicating oncolytic virus for cancer virotherapy. As more is learned about the functions of viral gene products in controlling the mammalian cell cycle and in disabling cellular defence mechanisms, specific viral functions can be augmented or eliminated to enhance antitumour efficacy and improve tumour cell targeting. General mechanisms by which this oncolytic virus achieves the antitumour efficacy and specificity are reviewed. Specifically, the deletion of the viral genes for thymidine kinase and vaccinia growth factor resulted in a vaccinia mutant with enhanced tumour targeting activity and fully retaining its efficiency of replication in cancer cells. Other potential strategies for improving this vector for gene delivery will also be discussed in this review.

Animals↗

PubMed2006

Current status of gene delivery and gene therapy in lacrimal gland using viral vectors.

Gene delivery is one of the biggest challenges in the field of gene therapy. It involves the efficient transfer of transgenes into somatic cells for therapeutic purposes. A few major drawbacks in gene delivery include inefficient gene transfer and lack of sustained transgene expression. However, the classical method of using viral vectors for gene transfer has circumvented some of these issues. 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. The transfer of genetic material into lacrimal epithelial cells and tissues, both in vitro and in vivo, has been critical for the study of tear secretory mechanisms and autoimmunity of the lacrimal gland. These studies will help in the development of therapeutic interventions for autoimmune disorders such as Sjögren's syndrome and dry eye syndromes which are associated with lacrimal dysfunction. These studies are also critical for future endeavors which utilize the lacrimal gland as a reservoir for the production of therapeutic factors which can be released in tears, providing treatment for diseases of the cornea and posterior segment. This review will discuss the developments related to gene delivery and gene therapy in the lacrimal gland using several viral vector systems.

Animals↗

PubMed2004

Gene delivery systems--gene therapy vectors for cystic fibrosis.

Gene delivery systems (GDS) play a central role in the development of gene therapy strategies for Cystic Fibrosis (CF). Further, these systems are important tools in studies with cultured cells and in animal models. In this review, we describe the properties of several viral and synthetic gene delivery systems, and evaluate their possible application in gene therapy of CF. While many gene delivery systems give satisfactory results in cultured or animal studies, none of these systems has been shown to fulfil all the requirements of safety and efficacy for use in CF patients. The intact airway epithelium, the most important target in CF gene therapy, proves to be well protected against invading vector systems.

Adenoviridae↗

PubMed2001

Gene delivery and gene therapy with herpes simplex virus-based vectors.

The development of efficient means of delivery genes in vivo is essential both for testing gene function in the intact animal and for human gene therapy procedures. A number of viral and non-viral gene delivery methods have been developed for this purpose. Of those herpes simplex virus (HSV)-based vectors have particular advantages for gene delivery to the nervous system including their ability to infect non-dividing neurones and establish asymptomatic latent infections. Moreover, considerable progress has been made, firstly, in disabling HSV vectors so as to prevent the damaging effects of wild type virus and secondly, to ensure long-term expression of the inserted transgene(s). These vectors thus offer a valuable tool for testing gene function in neuronal cells in vivo and may ultimately be safe enough for use in human gene therapy procedures.

Animals↗

PubMed2006

Surface adsorption of DNA to tissue engineering scaffolds for efficient gene delivery.

Gene delivery from tissue engineering scaffolds has potential to promote localized transgene expression that can induce the formation of functional tissues. Substrate-mediated delivery, an alternative delivery strategy to sustained release, is based on immobilization of DNA complexes to the polymer surface for subsequent delivery to cells cultured on the substrate. We investigate polyethylenimine (PEI)/DNA complex immobilization and subsequent cellular transfection on tissue engineering scaffolds fabricated from poly(lactide-co-glycolide) (PLG). The properties of the substrate and the complex affect both immobilization and cellular transfection. PLG promotes binding of PEI/DNA complexes, with percent bound independent of the N/P ratio or the DNA dosage. The levels of transgene expression are similar to or greater than control studies based on bolus DNA delivery, with orders of magnitude less DNA. Immobilization also homogeneously distributes the DNA throughout the scaffold, resulting in large numbers of transfected cells (>60%) at low surface quantities (<50 ng). Importantly, this approach can be employed to transfect cells throughout a three-dimensional scaffold. Tissue engineering scaffolds that are prefabricated into various shapes from a range of materials could potentially employ this strategy for numerous applications.

Adsorption↗

PubMed2006

Toxicity of cationic lipids and cationic polymers in gene delivery.

Gene therapy, as a promising therapeutics to treat genetic or acquired diseases, has achieved exciting development in the past two decades. Appropriate gene vectors can be crucial for gene transfer. Cationic lipids and polymers, the most important non-viral vectors, have many advantages over viral ones as non-immunogenic, easy to produce and not oncogenic. They hold the promise to replace viral vectors to be used in clinic. However, the toxicity is still an obstacle to the application of non-viral vectors to gene therapy. For overcoming the problem, many new cationic compounds have been developed. This article provides a review with respect to toxicity of cationic lipids and polymers in gene delivery. We evaluate the structural features of cationic compounds and summarize the relationship of toxicity and structure and hope to provide available suggestions on the development of these cationic compounds.

Animals↗

PubMed2000

Molecular adaptors for vascular-targeted adenoviral gene delivery.

Gene therapy would be considerably more effective if vectors could be targeted to specific organs or tissues after systemic administration. We previously developed an in vivo selection system to isolate organ- and tumor-homing peptides from phage display peptide libraries. The peptides isolated by this approach bind to receptors expressed in vascular endothelia. We describe here the development of molecular adaptors to target adenoviral gene therapy vectors to selective vascular "addresses." The adaptor design consists of an organhoming peptide conjugated to an adenovirus-binding moiety. We isolated and characterized several monoclonal antibodies that bind to adenovirus type 5 (Ad5). Two of the antibodies neutralized Ad5 infection. We linked the Fab fragments of one of these antibodies to a synthetic lung-homing peptide (CGFECVRQCPERC or GFE-1 peptide) and tested the ability of the resulting bispecific conjugate to retarget Ad5. Cells that express the receptor for the GFE-1 peptide and are resistant to Ad5 infection were sensitized to recombinant Ad5 vectors in the presence of the Fab-GFE adaptor. Our findings indicate that selective gene therapy delivery may be developed on the basis of our vascular targeting technology.

Adenoviridae↗

PubMed2006

Gene delivery and gene therapy of prostate cancer.

Surgery, radiation or hormonal therapy are not adequate to control prostate cancer. Clearly, other novel treatment approaches, such as gene therapy, for advanced/recurrent disease are desperately needed to achieve long-term local control and particularly to develop effective systemic therapy for metastatic prostate cancer. In the last decade, significant progress in gene therapy for the treatment of localised prostate cancer has been demonstrated. A broad range of different gene therapy approaches, including cytolytic, immunological and corrective gene therapy, have been successfully applied for prostate cancer treatment in animal models, with translation into early clinical trials. In addition, a wide variety of viral and nonbiological gene delivery systems are available for basic and clinical research. Gene therapy approaches that have been developed for the treatment of prostate cancer are summarised.

Animals↗

PubMed2004

Cationic compounds used in lipoplexes and polyplexes for gene delivery.

Gene transfer represents an important advance in the treatment of both genetic and acquired diseases. Many cationic lipids and cationic polymers naturally occurred or synthesized have been used for gene transfer. They have the advantages over viral gene transfer as non-immunogenic, easy to produce and not oncogenic. These cationic compounds, however, have the major limitations of inefficient transfection and toxicity to cells. For overcoming these problems, many new cationic compounds were developed since the first cationic lipid, DOTMA, was found usage in gene therapy. This article reviews cationic lipids for gene therapy from chemistry viewpoint and we classify these compounds as monovalent cationic lipids, polyvalent cationic lipids, cationic polymers, guanidine containing compounds, cationic peptides and cholesterol containing compounds, and hope to provide suggestions on the development of this variety of cationic compounds through the discussion.

Cations↗

PubMed1991

Adenovirus enhancement of transferrin-polylysine-mediated gene delivery.

Gene transfer may be accomplished by the receptor-mediated endocytosis pathway using transferrin-polylysine conjugates. For some target cells, however, gene transfer by this vector is extremely limited, despite the presence of the appropriate surface receptors, a phenomenon attributed to lysosomal degradation of endosome-internalized conjugate-DNA complexes. To enhance DNA escape from the cell vesicle system and thus augment gene transfer by this route, we have used the capacity of adenoviruses to disrupt endosomes as part of their entry mechanism. Adenoviral infection augmented levels of gene transfer by transferrin-polylysine conjugates in a dose-dependent manner: levels of gene transfer of greater than 2000-fold above baseline were achieved. Use of the adenovirus in this context allowed enhanced levels of gene transfer in a variety of target cells, including cell lines otherwise refractory to gene transfer by transferrin-polylysine conjugates. This augmentation was based on adenoviral-mediated vesicle disruption, a process independent of viral gene expression. Thus, the development of specific mechanisms to effect release from the endosome in combination with gene transfer by the receptor-mediated endocytosis pathway will increase the utility of this delivery system by allowing high levels of gene expression in target cells.

Adenoviridae↗

PubMedDate not supplied

Dendritic cationic lipids with highly charged headgroups for efficient gene delivery.

Gene therapy is expected to lead to powerful new approaches for curing many diseases, a potential that is currently explored in worldwide clinical trials. Nonviral DNA delivery systems are desirable to overcome the inherent problems of viral vectors, but their current efficiency requires improvement and the understanding of their mechanism of action is incomplete. We have synthesized new multivalent cationic lipids with highly charged dendritic headgroups to probe the structure-transfection efficiency relationships of cationic liposome (CL)-DNA complexes, a prevalent nonviral vector. The lipid headgroups are constructed from ornithine cores and ornithine or carboxyspermine endgroups. The dendritic lipids were prepared on a gram scale, using a synthetic scheme that permits facile variation of the lipid building blocks headgroup, spacer, and hydrophobic moiety. They carry four to sixteen positive charges in their headgroups. Complexes of DNA with mixtures of the dendritic lipids and neutral 1,2-dioleoyl-sn-glycero phosphatidylcholine (DOPC) exhibit novel structures at high contents of the highly charged lipids, while the well-known lamellar phase is formed at high contents of DOPC. DNA complexes of the new dendritic lipids efficiently transfect mammalian cells in culture without cytotoxicity and, in contrast to lamellar complexes, maintain high transfection efficiency over a broad range of composition.

Animals↗

PubMed2002

Electro-gene-transfer: a new approach for muscle gene delivery.

Gene transfer into skeletal muscle cells by direct injection of naked plasmid DNA results in sustained gene expression. Intramuscular injection of plasmid DNA might thus be used to correct myopathies, to secrete locally or systematic therapeutic proteins and to elicit an immune response against specific antigens. However, the potential utility of this technique for gene application in humans is limited by the poor transduction efficiency and the low and highly variable level of gene expression. Different methods are thus being developed to increase the efficiency of gene transfer in muscles. It has been recently reported that a dramatic improvement of DNA transfer is achieved by applying an electric field to the muscle fibers subsequent to local DNA injection. Electro-gene-transfer increases gene expression by several orders of magnitude and strongly reduces interindividual variability. Electroinjection of genes encoding for secreted proteins resulted in sustained expression and disease correction in animal models of gene therapy. Moreover, the immunogenicity of DNA vaccines is dramatically increased when antigen-encoding plasmids are delivered by this technique. This technique may thus have broad and important applications in human gene therapy. This review provides a brief overview of the theory of electro-gene-transfer and describes parameters governing its efficiency in muscle. We also summarize the results obtained with electro-gene-transfer in animal models to date and the technical issues that must be solved before its use for human therapy can be considered.

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↗

PubMed2000

Effect of bile and pancreatic juice on adenoviral-mediated gene delivery: implications on the feasibility of gene delivery through ERCP.

Current research in gene delivery to the liver is focused on the intravenous, intraarterial, intraportal, or intratumoral route. Another possible route for gene delivery is via the common bile duct through endoscopic retrograde cholangiopancreatography (ERCP). Whether bile and pancreatic juice have any effect on gene delivery is not established. To evaluate the effect of bile and pancreatic juice on adenoviral-mediated gene delivery, liver and pancreatic cell lines were infected with a recombinant adenovirus expressing an E. coli beta-galactosidase gene under the control of a cytomegalovirus promoter (rAdCMVpLacZ) in the absence or presence of various concentrations of bile and pancreatic juice. The proportion of cells infected was evaluated through X-gal staining. The toxicity of bile and pancreatic juice was also evaluated through cell morphology and detachment. Bile appeared to induce significant cytotoxicity in HepG2 and Huh7 cells (50% viability with 15 min of incubation). Neither bile nor pancreatic juice affected transgene expression. In the absence of bile/pancreatic juice, HepG2 (15-25%) and PANC-1 cells (10-18%) were less susceptible to rAdCMVpLacZ compared to Huh7 cells (75-84%, vs HepG2, P < 0.001) and BxPc-3 (82-95%, vs PANC-1, P < 0.001) at a multiplicity of infection (MOI) of 5. Bile reduced the transduction efficiency, but 5-10% HepG2 and 5-42% of Huh7 cells were still transduced in the presence of 80% bile for up to 10 min. Adenoviral-mediated gene delivery was reduced in the presence of pancreatic juice with a low multiplicity of infection (MOI of 5), but this effect was negated with an MOI of 50. These data provide encouragement to develop adenoviral-mediated gene delivery through ERCP.

Adenoviridae↗

PubMed1999

Sustained enhancement of liposome-mediated gene delivery and gene expression in human breast tumour cells by ionizing radiation.

PURPOSE: To investigate whether irradiation improves the delivery and expression of liposome-DNA complexes in human breast tumour cells. MATERIALS AND METHODS. MDA-MB231 and MCF-7 human breast tumour cells were transfected with a liposomal SV40-luciferase complex and irradiated immediately after, at 24h after or 24h prior to transfection and in the presence or absence of serum. The amount of luciferase plasmid in the cell was evaluated after extraction by the Hirt procedure, while luciferase expression was measured using a luminescence assay. RESULTS: Ionizing radiation enhanced the liposome-mediated delivery and expression of the SV40-luciferase transgene in MDA-MB231 breast tumour cells both in the absence and presence of serum as well as in MCF-7 breast tumour cells. Improved transgene delivery and expression was observed at a clinically relevant dose of 2 Gy, and was dose-dependent over a dose range of 2-10 Gy. The effects of irradiation on transgene expression were observed with irradiation immediately prior to exposure of the cells to the liposome-transgene complex, with irradiation up to 24 h before or up to 24 h after initiation of exposure. CONCLUSIONS: Irradiation at 24 h prior to exposure of breast tumour cells to the liposome-transgene complex appears to be the optimal approach for enhancing transgene delivery and expression. These findings suggest that ionizing radiation could promote the utility of gene therapy in the treatment of breast cancer.

Breast Neoplasms↗