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At least 541 records · Page 30Linked to original sources
PubMed2003

Gene therapy progress and prospects: gene therapy for severe combined immunodeficiency.

Severe combined immunodeficiencies have long been targeted as a group of disorders amenable to gene therapy because of their defined molecular biology and pathophysiology, and the prediction that corrected cells would have profound growth and survival advantage. Recently, several clinical studies have shown that conventional gene transfer technology can produce major beneficial therapeutic effects in these patients, but, as for all cellular and pharmacological treatment approaches, with a finite potential for toxicity.

Adenosine Deaminase↗
PubMed1997

Complementation of a primer binding site-impaired murine leukemia virus-derived retroviral vector by a genetically engineered tRNA-like primer.

Reverse transcription of retroviral genomes is primed by a tRNA annealed to an 18-nucleotide primer binding site. Here, we present a primer complementation system to study molecular interaction of the replication machinery with the primer and primer binding site in vivo. Introduction of eight base substitutions into the primer binding site of a murine leukemia virus-based vector allowed efficient RNA encapsidation but resulted in severely reduced vector replication capacity. Replication was restored upon complementation with a synthetic gene designed to encode a complementary tRNA-like primer, but not with a noncomplementary tRNA-like molecule. The engineered primer was shown to be involved in both the initiation of first-strand synthesis and second-strand transfer. These results provide an in vivo demonstration that the retroviral replication machinery may recognize sequence complementarity rather than actual primer binding site and 3' primer sequences. Use of mutated primer binding site vectors replicating via engineered primers may add additional control features to retroviral gene transfer technology.

Animals↗
PubMed2000

Transgene-mediated modifications to animal biochemistry.

The application of gene-transfer technology to domestic animals provides a way for the introduction of genes encoding biochemical pathways that are currently nonfunctional in these animals. This might provide a mechanism for increasing the availability of specific substrates that currently limit certain production characteristics, such as the production of wool. The progress and problems associated with recent attempts to transfer a cysteine biosynthetic pathway and a glyoxylate cycle to sheep are discussed, in addition to the extension of this concept to other biochemical pathways.

Animals↗
PubMed1998

Strategies of gene transfer to the kidney.

Kidney targeted gene transfer has been a realistic goal for many researchers since 1991, but unfortunately, to date there is no reliable gene transfer technique for gene therapy of renal diseases. However, at the experimental level, several in vivo gene transfer methods have attempted to target certain renal structures, for example, the HVJ-liposome method and renal perfusion of adenovirus for glomerular cells, intravenous injection of oligonucleotides (ODNs) for proximal tubule, intra-arterial injection of adenovirus followed by cold incubation with a vasodilator for interstitial vasculature of the outer medulla, and adenoviral injection into the renal pelvis for the inner medullary collecting duct. As an ex vivo gene transfer method targeting the glomerulus, the transfusion of genetically-modified mesangial cells has been attempted. Implantation of genetically-modified tubular epithelial cells into the subcapsular region has been employed for ex vivo transfection to the interstitium. Gene therapy has focused particularly on the transplanted kidney, where an exogenous gene can transferred in advance. In the future, an inducible system and individual cell targeting strategy should be developed. The improvement of gene transfer techniques, especially vectors for delivering genes, is crucial. The potential application of gene transfer technologies is enormous while the therapeutic approaches have just begun to be explored. Therapeutic interventions of the process of progression of glomerulonephritis in the rat have been directed towards inhibiting the actions of growth factors. Obviously, molecular biological intervention is coming of age and there is a tremendous excitement over its potential. We believe that gene transfer techniques will become common tools for the dissection of molecular aspects of diseases and possibly for gene therapy in the field of nephrology.

Animals↗
PubMed2001

Ngi and Internet2: accelerating the creation of tomorrow's internet.

Internet2 is a consortium of leading U.S. universities working in partnership with industry and the U.S. government's Next Generation Internet (NGI) initiative to develop a faster, more reliable Internet for research and education including enhanced, high-performance networking services and the advanced applications that are enabled by those services [1]. By facilitating and coordinating the development, deployment, operation, and technology transfer of advanced, network-based applications and network services, Internet2 and NGI are working together to fundamentally change the way scientists, engineers, clinicians, and others work together. [http://www.internet2.edu] The NGI Program has three tracks: research, network testbeds, and applications. The aim of the research track is to promote experimentation with the next generation of network technologies. The network testbed track aims to develop next generation network testbeds to connect universities and federal research institutions at speeds that are sufficient to demonstrate new technologies and support future research. The aim of the applications track is to demonstrate new applications, enabled by the NGI networks, to meet important national goals and missions [2]. [http://www.ngi.gov/] The Internet2/NGI backbone networks, Abilene and vBNS (very high performance Backbone Network Service), provide the basis of collaboration and development for a new breed of advanced medical applications. Academic medical centers leverage the resources available throughout the Internet2 high-performance networking community for high-capacity broadband and selectable quality of service to make effective use of national repositories. The Internet2 Health Sciences Initiative enables a new generation of emerging medical applications whose architecture and development have been restricted by or are beyond the constraints of traditional Internet environments. These initiatives facilitate a variety of activities to foster the development and deployment of emerging applications that meet the requirements of clinical practice, medical and related biological research, education, and medical awareness throughout the public sector. Medical applications that work with high performance networks and supercomputing capabilities offer exciting new solutions for the medical industry. Internet2 and NGI,strive to combine the expertise of their constituents to establish a distributed knowledge system for achieving innovation in research, teaching, learning, and clinical care.

Internet↗
PubMed2003

[Gene-enhanced tissue engineering: applications in osteoinduction using cultured mesenchymal stem cells transduced with the bFGF gene].

To investigate the effect of basic fibroblast growth factor(bFGF) gene transfection on the proliferation and differentiation of mesenchymal stem cells (MSCs) and to provide basis for accelerating bone defect repairing using gene-enhanced tissue engineering technology, Rabbit periosteum-derived MSCs were transfected with the full-length rat bFGF cDNA in vitro. The transient and stable gene expression of bFGF were determined by immunohistochemistry. The proliferation and the synthesis alkaline phosphatase (ALP) and osteocalcin(OC) of the transfected MSCs were also examined. The results showed that bFGF cDNA could be transferred into osteoblasts and expressed stably at least 4 weeks. The proliferation and OC content of genetically modified MSCs were increased significantly, whereas the ALP activity remained no change. In conclusion, transfer of gene encoding bFGF to MSCs increases its proliferation and osteogenesis property. Based on the successful conjunction of the existing techniques of tissue engineering with the novel possibilities offered by modern gene transfer technology, an innovative concept, molecular tissue engineering, was put forward for the first time. As a new branch of tissue engineering, it represents both a new area and an important trend in tissue engineering research.

Alkaline Phosphatase↗
PubMed1998

In vivo gene transfer into the adult mammalian central nervous system by continuous injection of plasmid DNA-cationic liposome complex.

Previously reported methods of liposome-mediated direct in vivo gene transfer have been inefficient, especially when performed with highly differentiated, quiescent cells of the adult mammalian central nervous system (CNS). We have therefore improved these procedures based upon a novel concept. Following continuous injection of plasmid DNA-cationic liposome complex which contained a reporter gene encoding E. coli beta-galactosidase into the striatum of adult rats, the expression of transgene was dramatically elevated without any adverse effects. This new technique may enable a wide application of liposome-mediated gene transfer technology not only to basic analysis of gene functions in the brain but also for clinical treatment of certain CNS disorders.

Animals↗
PubMed1999

Retroviral vector-mediated gene expression in hematopoietic cells.

Gene transfer vectors based on simple retroviruses and more complex lentiviruses are currently the most reliable tools for stable establishment of transgenes in hematopoietic cells. While important hurdles in basic gene transfer technologies have been overcome in recent years, there is still some uncertainty in the choice of the cis-regulatory elements of the vector. These elements dictate the overall level, clonal variability, response to differentiation and persistence of transgene expression in vivo and thus have a significant influence on the outcome of therapeutic applications of somatic gene transfer. The rationale underlying the further improvement of such cis-elements is reviewed here.

Animals↗
PubMed2000

Adenovirus-mediated transfer of regulable gene expression.

The past several years have seen significant progress in the development of adenoviral vectors with markedly decreased pathological potential and greatly increased capacity for incorporation of foreign DNA. Paralleling these developments in gene transfer technology have been remarkable advances in both the design and optimization of gene regulatory systems. Ultimately, the goal of these gene regulatory systems is control of transgene expression in vivo by the administration of an exogenous compound. With the prospect of clinical human gene therapy on the horizon, the co-evolution of safe and efficient gene transfer strategies, with effective regulation of transgene expression, represents an essential step towards therapeutically viable gene transfer protocols. This review introduces recent advances in both adenoviral-based vectors and gene regulatory systems, and examines those studies in which adenoviral vectors and gene-regulatory systems have been combined in vivo.

Adenoviridae↗
PubMed1992

[Gene transfer and gene therapy].

The application of gene transfer technology to human gene therapy has been intensively investigated during the last decade. The first human clinical trials in adenosine deaminase deficiency and metastatic melanoma recently demonstrated the feasibility and safety of using retroviral gene transduction for human gene therapy. Many problems remain to be solved for a better understanding of the functioning of genes to be transferred, a better efficiency of gene transfer and genetic correction by site-specific targeting in vivo, a better knowledge of the biological properties of target cells such as totipotent hematopoïetic stem cells. Clinical developments are expected in genetic diseases (immunodeficiency, thalassemia, hemophilia) and non genetic disorders (lymphokine gene therapy for cancer).

Child↗
PubMed1998

Application of the Method of Organizational Congruencies in Substituting Organic Solvents With Vegetable Agents for the Cleaning of an Offset Printing Machine.

The aim of this research is the application of the Method of Organizational Congruencies before and after the substitution of organic solvents with vegetable agents for the cleaning of an offset printing machine in order to assess the organizational changes. A solvent-free process is the goal of the Subsprint Project (Technology Transfer Program of the European Community). This study shows how human and environmental health is improved by using vegetable agents, though this change may lead to some other organizational constraints such as an increase of the time needed, monotony, and repetitiveness of the technical actions involved. The authors underline that the knowledge of the impact of the new technology on health helps a better understanding of the resistance to the change and its further amelioration.

Journal Article↗
PubMed2001

Developmental consequences of embryo and cell manipulation in mice and farm animals.

Advances in biotechnology in recent decades have revolutionized our understanding of early mammalian development and promise to provide ever more finely tuned and precisely targeted techniques for genetic enhancement of domestic animal species. In demonstrating what is both technically and biologically possible, not only in mice but also in larger animal species, research has provided hope that previously intractable diseases and genetic defects can be successfully combated. Crucial to this research is the ability to culture oocytes, embryos and somatic cells in vitro and to sustain their development without inducing adverse short- or long-term consequences. There is a need to refine current culture strategies in farm animal species to avoid jeopardizing their dependent technologies. A key to resolving current limitations of culture strategies is to identify, acknowledge and then address those features of in vitro culture that compromise early regulation of mammalian development. The aim of this review is to appraise critically in vitro embryo and somatic cell production strategies in the context of their impact on developmental competence and normality at embryonic, fetal and later stages. In addition, effects of physically manipulating embryos and cells, most notably via nuclear and gene transfer technologies, are considered with a view to identifying how detrimental consequences can be avoided.

Animals↗
PubMed1996

Bicistronic and two-gene retroviral vectors for using MDR1 as a selectable marker and a therapeutic gene.

We describe a series of two-gene and bicistronic retroviral vectors that use the human MDR1 gene as a selectable marker for the overexpression of a second heterologous gene in transduced cells. The vectors use Harvey murine sarcoma virus sequences for viral expression and packaging functions and include sites for cloning foreign genes of interest under the control of either an internal promoter (two-gene vectors) or an internal ribosome entry site (bicistronic vectors). To characterize these vectors, we used neo as a reporter gene for foreign gene expression and as an independently selectable marker for comparison with MDR1. Each of the vector constructions supported high-titer retrovirus production and transduction of mouse and human cell lines. Using MDR1-neo virus supernatants in parallel titering assays, we found that titers based on colchicine resistance were 10- to 20-fold lower than titers based on G418 resistance, suggesting that MDR1 is a more stringent selectable marker than neo in NIH 3T3 and KB-3-1 cell lines. Whereas neo gene expression with the two-gene vectors was subject to host-specific limitations on internal promoter activity, the bicistronic vectors were highly active in three cell lines tested. In K562 cells, using the bicistronic vector, selection with colchicine led to at least 20-fold higher expression of the MDR1 gene product than did selection with G418, suggesting that the stringent MDR1 selection system is very efficient for obtaining overexpression of foreign genes. Retroviral vectors carrying MDR1 as a selectable marker plus a second, heterologous gene of interest could have widespread utility for in vitro and in vivo applications of gene transfer technology, including gene therapy.

3T3 Cells↗
PubMed2003

Applied gene therapy in preclinical models of vascular injury.

Atherosclerosis remains the major cause of morbidity and mortality in Western countries. Atherothrombotic complications, including vascular occlusions and severe narrowing of nutrient blood vessels in the cerebral, coronary, or peripheral circulation, usually require invasive revascularization strategies. As molecular mediators contributing to these complications are being identified in more representative experimental injury models, and as gene transfer platforms and vectors acquire improved safety and efficacy profiles, there is ground for cautious optimism that gene-based interventions will likely reduce the clinical burden of these diseases. Increased generation of reactive oxygen species in diseased atherosclerotic vessels has been implicated in vasospasm, exaggerated neointima formation, and enhanced thrombosis. Ex vivo pressurized vascular gene transfer in venous bypass grafts using antisense oligonucleotides directed against cell-cycle control genes can modify the venous graft's phenotype and confer clinical benefit with improved long-term graft survival. Alternatively, percutaneous intra-arterial gene transfer is feasible, but at relatively low transgene expression levels. Although this may suffice in the case of secreted gene products with marked paracrine or bystander effects, including nitric oxide synthase and heme oxygenase-1, drug- and gene-eluting stents may provide the preferred future vehicle for well-controlled, quantifiable, and safe vascular gene transfer. Continued efforts to improve gene transfer technology in diseased human vessels and to increase our understanding of molecular targets are required before the full therapeutic potential of vascular gene therapy can be realized.

Animals↗
PubMed2001

[Gene therapy in ophthalmology. Review of options and trends in corneal diseases].

BACKGROUND: Gene therapy has gained increasing attention and a number of ongoing clinical trials have been initiated. This article provides current perspectives and limitations on gene therapy in ophthalmology. Since a number of comprehensive studies on gene therapy for retinal diseases already exist, we focus attention to the treatment of anterior segment disorders of the eye. MATERIAL AND METHODS: We undertook a reference search (DIMDI, PubMed) of articles published between (1989-2000) using the key words cornea, conjunctiva, eye, gene therapy, and keratoplasty. The search was restricted to publications in English, French and German. In addition, we incorporated some results of our recent experiments on cytokine gene transfer to the cornea. RESULTS: Attention to gene therapy in ophthalmology is currently focused on retina and choroidea (40 articles) however, an increasing number of publications includes the cornea (12 articles). The majority of these contributions deals with improvements in the design of gene therapy vectors in particular for targeted application. CONCLUSIONS: Gene therapy to the cornea may offer interesting new venues. Currently, insufficient gene transfer technologies and safety concerns prevent the broad application in humans. However, a broad spectrum of applications can be supposed.

Corneal Diseases↗
PubMed2006

Calves born from anestrus yaks (Poephagus grunniens L.) subjected to Ovsynch and superovulation treatment.

An attempt was made to induce estrus and ovulation in eight anestrus yaks by use of the Ovsynch protocol. Six out of eight yaks were successfully induced into estrus, and ovulation occurred in all the responding yaks 1-2 days after the second GnRH administration. Out of the six animals that responded to the treatment, two mated naturally with yak bulls, and calves were obtained from them. The other four animals were further administered a superovulatory regimen of Folltropin (FSH-P). Following Folltropin and Ilerin (a PGF(2alpha) analog) treatment, the animals were subjected to natural insemination. Only one animal in which natural mating occurred was flushed non-surgically for embryo recovery 7 days post-insemination. Thereafter, all the donor animals were administered with Ilerin. After 48-72 h, they came into heat and mated naturally with yak bulls, and calves were obtained from them after expiration of the normal gestation period. Following superovulation, the average numbers of palpable corpora lutea in the right and left ovaries were 2.25+/-0.6 and 1.75 +/-0.3, respectively. Three embryos were recovered by non-surgical flushing from a single animal. One embryo was transferred to a recipient yak, who produced one female calf after 258 days. This is the first report of production of a yak calf through embryo transfer-technology.

Anestrus↗
PubMedDate not supplied

Gene transfer into the adult kidney for unravelling disease processes.

Insights into the pathogenesis of human disease must be based on an understanding of the molecular mechanisms that regulate the structure and function of individual organs. For this purpose, gene transfer technologies provide powerful and attractive tools. In principle, two different approaches are feasible to identify pathophysiological roles of certain genes: 'gain-of-function', and 'loss-of-function'. The former examines consequences of overexpression of an exogenous gene, and the latter investigates the outcomes of inhibition of a particular molecule via antisense, decoy, ribozyme and dominant-negative strategies. Gene transfer to specific renal structures allows evaluation of in vivo effects of certain molecules on the structure and function of each nephron segment. It would also be useful for therapeutic intervention in renal diseases through introduction of therapeutically relevant genes into affected sites. This article summarizes current experience with renal gene transfer and addresses its potential impacts on the understanding of renal function in vivo.

Adult↗
PubMed2003

Frontiers in gene therapy for erectile dysfunction.

Complete sequencing of the human genome has made possible a new age of molecular medicine. The utilization of sophisticated genomic technologies has important implications to the understanding, diagnosis and treatment of erectile dysfunction. This report will review one aspect of the impact of the genomic revolution on urology, to wit, the preclinical evidence emerging from several laboratories indicating that gene therapy for erectile dysfunction may well provide the first safe and effective application of gene therapy to the treatment of human smooth muscle disease. The molecular targets explored thus far have concentrated largely on manipulating various aspects of the nitric oxide/guanylate cyclase/cGMP system, although genetic modulation of growth factors, calcium sensitization mechanisms and potassium channel expression have also been explored. Cell-based gene therapy techniques are also being explored. The apparent preclinical success of virtually all of these gene-based strategies reflects the multifactorial nature of erectile disease as well as the numerous regulatory mechanisms available for restoring erectile capacity. While technical hurdles remain with respect to the choice of delivery vectors, molecular target validation and duration of efficacy, 'proof-of-concept' has clearly been documented. The ultimate goal of gene therapy is to provide a safe, effective and specific means for altering intracavernous pressure 'on demand', while simultaneously eliminating the necessity for other forms of therapy, and moreover, without altering resting penile function, or the physiology of other organ systems. It is in these arenas that the groundbreaking potential of gene transfer technology to the treatment of erectile dysfunction will be fully tested. In fact, the potential benefits of the application of gene transfer techniques to this important medical problem is just now beginning to be appreciated/recognized.

Erectile Dysfunction↗