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PubMed1998

Potential benefits of cell cloning for human medicine.

The successful cloning of a mammal from an adult somatic cell nucleus opens new avenues for major advances in reproductive medicine, biotechnology and cellular-based transplantation therapies for degenerative diseases. At the same time, this breakthrough has generated much heated discussion concerning the ethics of cloning. Twinning is a form of cloning, and there are instances in clinical assisted reproduction in which the deliberate formation of twins by embryo dissection would seem ethically acceptable. Nuclear transfer technology might facilitate the derivation of human embryonic stem cells, capable of differentiation into a wide variety of somatic cell lineages. Directed differentiation of human embryonic stem cells into specific cell types in vitro could provide a universal source of cells for transplantation therapy. The potential benefits of therapeutics based on cloning technologies are considerable, and hasty legislation to ban all such procedures could block progress in critical arenas of biomedical research.

Animals↗
PubMed2005

International egg-sharing to provide donor oocytes for clinical assisted reproduction and derivation of nuclear transfer stem cells.

Recent advances in nuclear transfer technology for derivation of patient-specific stem cells have opened up new avenues of therapy for various human diseases. However, a major bottleneck is the severe shortage of human donor oocytes. Egg-sharing in return for subsidized fertility treatment has been suggested as an ethically justifiable and practical solution to ease the shortage of donor oocytes both for derivation of nuclear transfer stem cells and assisted reproduction. However, it is envisioned that many patients would be more comfortable with their supernumerary oocytes going into derivation of nuclear transfer stem cells, rather than having another potential anonymous offspring in assisted reproduction. Nevertheless in more economically developed countries, fertility treatment is easily affordable to a large segment of the population, which reduces the pool of available egg-sharers. In less affluent countries, fertility treatment is often beyond the financial resources of most sub-fertile couples. Hence, a possible solution may be to allow egg-sharing across international borders. Potential egg-sharers would come from less economically-developed countries that are more in need of financial subsidies for sub-fertile couples seeking clinically assisted conception. This is ethically justifiable because it makes fertility treatment affordable to childless couples from poorer countries, while at the same time easing the shortage of donor oocytes in more affluent countries.

Cloning, Organism↗
PubMed2005

Point of care biomedical sensors.

With the development of critical areas of interdisciplinary research, scientists will lead to an enhanced understanding and control of the key processing stages involved in the design and manufacture of sensor-and electrode-based micro-devices such as micro total analysis systems (muTAS), bio-chips, bio-arrays and DNA sensors. It is anticipated that this fundamental work will lead to tangible technology transfer in the areas of blood analysis, cardiac enzyme detectors, liver and renal function, infectious diseases, gene disorders, etc. These will obviously have major benefits to healthcare delivery. The development of miniaturised, integrated sensor/electrode-based devices are revolutionising both the delivery of health care. In this paper, some of the most exciting research themes in these areas are identified, as well as novel underpinning fabrication technologies and transduction principles, which should make future advances possible.

Biomedical Technology↗
PubMed2001

Use of homogeneous time-resolved fluorescence energy transfer in the measurement of nuclear receptor activation.

Nuclear receptors (NRs) are a superfamily of ligand-dependent transcription factors that mediate the effects of hormones and other endogenous ligands to regulate the expression of specific genes. NRs are clearly important targets for drug discovery. Ligand-dependent protein-protein interactions between NRs and NR coactivators (NRCoAs) are a critical step in regulation of transcription. Homogeneous time-resolved fluorescence (HTRF) energy transfer technology is sensitive, homogeneous, and nonradioactive. These characteristics make this approach attractive for developing high-throughput screening assays. The long-lived nature of the fluorescence of europium cryptate combined with a time delay in reading facilitates the homogeneous nature of the assay. Importantly, the introduction of lanthanides (with R0 values as great as 90 A in HTRF) make HTRF amenable to be used for protein-protein interactions. In this article we review, using peroxisome proliferator-activated receptor (PPAR)gamma as a model system, a novel approach for characterizing the ligand-dependent interaction between NR and NRCoA using HTRF technology and its potential uses in small-molecule screening, profiling selectivity of NR-NRCoA paired interactions, and profiling NR ligands as agonists versus partial agonists or antagonists.

CREB-Binding Protein↗
PubMed1997

Functional consequences of adenovirus-mediated murine pancreatic gene transfer.

Pancreatic adenoviral gene transfer can be achieved with high efficiency; however, questions concerning tissue injury from this commonly used vector have not been addressed. In these experiments, the effects of adenoviral gene transfer on pancreatic exocrine function were evaluated. Direct pancreatic injection with an adenoviral vector containing the Escherichia coli beta-galactosidase (beta-Gal; lacZ) transgene (H5.010CBlacZ) resulted in a high level of transgene expression (64 +/- 6% of pancreatic cells expressed beta-Gal) at 3 days following infection. However, amylase levels in four of five different subcellular pancreatic fractions were significantly decreased at this time point. Direct pancreatic injection with either saline or psoralen/UV-inactivated adenovirus did not have this effect, whereas both transduction with an adenoviral vector containing a different transgene and transduction with a homologous transgene resulted in decreased pancreatic amylase. The decrease in subcellular amylase levels persisted at 7 days post-transduction, and then returned to baseline at 21 days post-transduction. There was associated histologic damage (increased edema, inflammation, cell destruction, and vacuolization) at 3 and 7 days post-transduction, which resolved by 21 days. In summary, adenoviral transduction of the pancreas results in increased viral transgene expression and a uniform decrease in host amylase production throughout the pancreas. The normalization of amylase levels and histology suggest that organ recovery occurs. Gene transfer technology as a novel strategy for pancreatic diseases such as diabetes, pancreatitis, and cystic fibrosis is feasible but will benefit from continued approaches to limit toxicity.

Adenoviridae↗
PubMed1998

Cytokine gene transfer in cancer therapy.

New strategies based on gene transfer technology are employed in cancer therapy. Cytokines are polypeptides involved in immunity and inflammation, and essentially control the magnitude of the immune response. Genetically modified tumor cells releasing various cytokines have been shown to enhance tumor immunogenicity and to induce the regression of preexisting tumors. In some instances, immunological memory has been generated to resist the subsequent challenge with unmodified, parental tumor cells. Cytokine gene transfer into antitumor effector cells, as well as antigen presenting cells, is also being investigated to augment antitumor immune responses.

Animals↗
PubMed2006

Indica rice (Oryza sativa, BR29 and IR64).

Rice is the world's most important food crop. Indica-type rice provides the staple food for more than half of the world population. To satisfy the growing demand of the ever-increasing population, more sustained production of indica-type rice is needed. In addition, because of the high per capita consumption of indica rice, improvement of any traits including its nutritive value may have a significant positive health outcome for the rice-consuming population. Rice yield productivity is greatly affected by different biotic stresses, like diseases and insect pests, and abiotic stresses like drought, cold, and salinity. Attempts to improve resistance in rice to these stresses by conventional breeding through introgression of traits have limited success owing to a lack of resistance germplasm in the wild relatives. Gene transfer technology with genes from other sources can be used to make rice plants resistant or tolerant to insect pests, diseases, and different environmental stresses. For improving the nutritional value of the edible endosperm part of the rice, genes for increasing iron, beta-carotene, or better quality protein can be introduced in rice plants by genetic engineering. Different crops have been transformed using various gene transfer methods, such as protoplast transformation, biolistic, and Agrobacterium-mediated transformation. This chapter describes the Agrobacterium-mediated transformation protocol for indica-type rice. The selectable marker genes used are hygromycin phosphotransferase (hpt), neomycin phosphotransferase (nptII), or phosphomannose isomerase (pmi), and, accordingly, the selection agents are hygromycin, kanamycin (G418), or mannose, respectively.

Adaptation, Physiological↗
PubMed2005

Interleukin-4 gene transfer into rat pancreas by recombinant adenovirus.

OBJECTIVE: Adenovirus-mediated gene transfer technology may provide a novel approach in the treatment of pancreatic diseases. In the rat model of chronic pancreatitis induced by dibutyltin dichloride (DBTC), Th1 lymphocytes are known to be involved in the mediation of inflammation. We therefore investigated whether local expression of the Th2 cytokine interleukin (IL)-4 might modulate the inflammatory response. To address this question, we have established a protocol of efficient gene transfer into rat pancreas. MATERIAL AND METHODS: Recombinant adenovirus constructs carrying the Escherichia coli beta-galactosidase gene (Adbeta-gal) or the rat IL-4 gene (AdrIL-4) were injected into the left gastric artery of healthy LEW.1W rats. Expression of beta-Gal and IL-4 in pancreatic cells was analyzed by X-Gal staining and reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. After optimization of the transduction protocol, effects of the IL-4 gene transfer on pancreatic inflammation and fibrosis were studied in DBTC-treated rats. RESULTS: Seven days after Adbeta-gal injection, beta-gal-positive cells were detectable in the rat pancreas. RT-PCR analysis using RNA from pancreata of AdrIL-4-treated rats indicated that IL-4 was expressed for at least 14 days after adenovirus application. Expression of the IL-4 transgene was accompanied by a transient increase of the IL-10 mRNA level in the pancreas. In DBTC-treated rats, adenovirus-mediated transfer of the IL-4 gene modified the pattern of infiltrating inflammatory cells in the pancreas. Importantly, a decrease of CD4+ helper cells was observed. CONCLUSIONS: Our data suggest that the injection of recombinant adenoviruses into the left gastric artery is a promising approach to achieving expression of therapeutic transgenes in the pancreas.

Adenoviridae↗
PubMed1995

Gene targeting and gene transfer studies of the plasminogen/plasmin system: implications in thrombosis, hemostasis, neointima formation, and atherosclerosis.

The plasminogen/plasmin or fibrinolytic system with its physiological triggers, tissue-type plasminogen activator, and urokinase-type plasminogen activator has been presumed to participate in normal and pathological processes of the vessel wall such as blood clot dissolution (thrombolysis), hemostasis, aneurysm formation, neovascularization, restenosis, and atherosclerosis. The implied role of the fibrinolytic system in vivo is, however, deduced from correlations between fibrinolytic activity and (patho)physiological phenomena, which does not allow establishing a cause/consequence relationship. Gene targeting and gene transfer technologies allow establishment of the in vivo role of gene products more conclusively. This article reviews briefly the findings of such studies on thrombolysis/thrombosis, hemostasis, neointima formation, atherosclerosis, and associated effects on survival.

Arteriosclerosis↗
PubMed2004

Gene transfer to epidermal stem cells: implications for tissue engineering.

The skin is an attractive target for gene therapy because it is easily accessible and shows great potential as an ectopic site for protein delivery in vivo. Genetically modified epidermal cells can be used to engineer three-dimensional skin substitutes, which when transplanted can act as in vivo 'bioreactors' for delivery of therapeutic proteins locally or systemically. Although some gene transfer technologies have the potential to afford permanent genetic modification, differentiation and eventual loss of genetically modified cells from the epidermis results in temporary transgene expression. Therefore, to achieve stable long-term gene expression, it is critical to deliver genes to epidermal stem cells, which possess unlimited growth potential and self-renewal capacity. This review discusses the recent advances in epidermal stem cell isolation, gene transfer and engineering of skin substitutes. Recent efforts that employ gene therapy and tissue engineering for the treatment of genetic diseases, chronic wounds and systemic disorders, such as leptin deficiency or diabetes, are reviewed. Finally, the use of gene-modified tissue-engineered skin as a biological model for understanding tissue development, wound healing and epithelial carcinogenesis is also discussed.

Animals↗
PubMed2002

Safety of the new generation recombinant factor concentrates.

Haemophilia A and B are X-linked disorders resulting from deficiency of Factor VIII and IX, respectively. Clinical sequellae of Factor VIII or IX deficiency include spontaneous and traumatic haemorrhages into joints, soft tissues, and muscles. The cornerstone of therapy has been replacement of the deficient factor, historically with pooled-plasma derivatives. The unfortunate blood-borne infection transmission (such as HIV, hepatitis B and C viruses), inhibitor formation, immunosuppression, and, in certain cases, thrombosis by these products has spawned major advances and innovations in the manufacture of clotting products. Recombinant technology has virtually eliminated transmissible disease risk; yet, the presence of albumin in second and third generation recombinant products raises, at the least, theoretical risk of prions and parvovirus B19. Other non-infectious complications, including inhibitor formation, allergic reactions, and thrombosis, remain formidable concerns. Despite this, recombinant factors remain the most attractive treatment approach for haemophilia. Future improvement awaits the development of safe and effective gene transfer technology.

Factor IX↗
PubMed2003

Improving successful pregnancies after embryo transfer.

Over the past 20 years the rate of blastocyst development in vitro has improved through the development of sequential defined media, refining the oxygen concentrations during culture and providing substrates to ameliorate free radical accumulation. Despite these advances there has been little progress in improving calving rates after the transfer of in vitro produced embryos. This suggests that the culture conditions have been very effective in enabling those fertilised oocytes to reach the blastocyst stage that otherwise would not occur in vivo. We suggest that the next advance by which the embryo transfer technology gains more acceptance in cattle production will be identifying those cows which are intrinsically superior recipients. This must be coupled to the development of non-invasive assessments of the developmental competence of both the oocyte and the blastocyst. Until these two goals are achieved the ET industry will remain static and unable to overcome the economic loss caused by embryo mortality occurring 7-10 days after transfer.

Abortion, Veterinary↗
PubMed1998

Direct gene transfer into the rat pancreas using DNA-liposomes.

BACKGROUND: Pancreatic cancer represents a malignancy with very poor clinical prognosis and limited therapeutic potential. Recent developments of gene transfer technology offer new therapeutic avenues by delivering recombinant genes directly into normal or neoplastic tissue in vivo. METHODS: Here we show that the LacZ marker gene, complexed to cationic liposomes, can be introduced into the pancreas by either intraductal or intra-arterial injection. Expression of the beta-galactosidase gene product was monitored by polymerase chain reaction and histochemistry. RESULTS: Up to 28 days after in vivo gene transfer, beta-galactosidase activity could be demonstrated in the pancreas. Intraductal application induced gene expression in lining duct cells preferentially. Twenty-four hours after intraductal injection of liposomes, a dose-dependent, transient increase in serum amylase levels was detected. Nevertheless, no histological signs of pancreatitis were evident. Intra-arterial injection resulted in beta-galactosidase expression in endothelial cells of intrapancreatic arteries, as well as in the spleen, lymph nodes and liver, but not in ductal cells of the pancreas. Only occasionally were acinar cells positive for blue staining by either type of treatment. CONCLUSION: These experiments demonstrate that in vivo gene transfer into the pancreas is feasible using DNA-liposome complexes. Furthermore, the route of administration largely determines cell type specificity and side-effects. This technique might have an impact for the development of gene therapy strategies for pancreatic diseases.

Amylases↗
PubMed2003

Gene therapy ethics and haemophilia: an inevitable therapeutic future?

Haemophilia was recognized early on as an ideal candidate for a gene transfer approach to therapy. In the past decade, gene transfer experimentation in the haemophilias has indeed played an integral role in furthering the science in the global field of gene therapy. However, these expectations have placed haemophilia gene transfer researchers under pressure to succeed in a scientific domain in which successes are infrequent and progress is necessarily slow. These same expectations have also fueled the perception of gene therapy as the inevitable therapeutic goal for the youngest children with haemophilia. In this paper, we will discuss the ethical implications of this perception in light of anticipated benefits, acceptable risk, perceived consumer need and the unknown cost of this intervention. A framework for the future study and therapeutic implementation of gene transfer technology in this specific population is proposed. Public debate on this issue that includes the voices of the intended beneficiaries, especially the parents of the youngest children with haemophilia and the children themselves, is encouraged.

Ethics, Clinical↗
PubMed1995

[Electrophoretic analysis of the protein patterns of the nuclear transplant rabbit embryos].

The qualitative patterns of protein synthesis in nuclear transplant rabbit embryos were examined by SDS-polyacrylamide gel electrophoresis followed by silver staining. The results indicated that the qualitative pattern of several protein synthesis in NT embryos was very different from the protein pattern of donor morulae or recipient oocytes, and also not as the same as the protein pattern obtained from fertilized ova at pronuclear formation stage. After fertilization or nuclear transfer, several maternal proteins were no longer synthesized or decreased in the embryo, and some new bands were observed and several protein synthesis were increased obviously. The most intriguing aspect of this study was the observation that all major changes in the protein pattern took place after fertilization or nuclear transfer and were rather similar. It is suggested that the gene activities of the donor nucleus from rabbit morulae are reprogrammed by the oocyte cytoplasm in current nuclear transfer technology, but the reprogramming is incomplete. This paper stresses on the paternal effect during fertilization on gene expression in nuclear transplant rabbit embryos.

Animals↗
PubMed2000

Insect pest management in tropical Asian irrigated rice.

Abundant natural enemies in tropical Asian irrigated rice usually prevent significant insect pest problems. Integrated pest management (IPM) extension education of depth and quality is required to discourage unnecessary insecticide use that upsets this natural balance, and to empower farmers as expert managers of a healthy paddy ecosystem. Farmers' skill and collaboration will be particularly important for sustainable exploitation of the potential of new, higher-yielding and pest-resistant rice. IPM "technology transfer" through training and visit (T&V) extension systems failed, although mass media campaigns encouraging farmer participatory research can reduce insecticide use. The "farmer first" approach of participatory nonformal education in farmer field schools, followed by community IPM activities emphasizing farmer-training-farmer and research by farmers, has had greater success in achieving IPM implementation. Extension challenges are a key topic for rice IPM research, and new pest management technology must promote, rather than endanger, ecological balance in rice paddies.

Animals↗
PubMed2005

Gene-induced chondrogenesis of primary mesenchymal stem cells in vitro.

Adult mesenchymal stem cells (MSCs) have the capacity to differentiate into various connective tissues such as cartilage and bone following stimulation with certain growth factors. However, less is known about the capacity of these cells to undergo chondrogenesis when these proteins are delivered via gene transfer. In this study, we investigated chondrogenesis of primary, bone marrow-derived MSCs in aggregate cultures following genetic modification with adenoviral vectors encoding chondrogenic growth factors. We found that adenoviral-mediated expression of TGF-beta1 and BMP-2, but not IGF-1, induced chondrogenesis of MSCs as evidenced by toluidine blue metachromasia and immunohistochemical detection of type II collagen. Chondrogenesis correlated with the level and duration of expressed protein and was strongest in aggregates expressing 10-100 ng/ml transgene product. Transgene expression in all aggregates was highly transient, showing a marked decrease after 7 days. Chondrogenesis was inhibited in aggregates modified to express >100 ng/ml TGF-beta1 or BMP-2; however, this was found to be partly due to the inhibitory effect of exposure to high adenoviral loads. Our findings indicate that parameters such as these are important functional considerations for adapting gene transfer technologies to induce chondrogenesis of MSCs.

Adenoviridae↗
PubMed2002

Polyethylenimine Derivatives as Potent Nonviral Vectors for Gene Transfer.

The delivery of a functional gene into a tissue can allow the correction of gene defaults or mutations such as those observed in severe hereditary pathologies or in cancer tissues and could lead to gene therapy. To achieve gene transfer, viral vectors are mainly used because of their intrinsic ability to enter the cells and promote expression of the transgene. However, many factors can limit the use of viral vectors, including a heavy laboratory infrastructure, and, in the case of iterative administration, the induction of immune response against viral proteins. Alternative gene transfer technologies based on nonviral vectors have been proposed. Polyethylenimine (PEI) derivatives are polycationic molecules that are able to form stable complexes with plasmidic DNA. PEI/DNA complexes attach to the cell surface, migrate into clumps that enter the cell by endocytosis and are deagregated in an acidic lysosomal compartment and/or enter the nucleus. PEI derivatives can be proposed as linear (22 kDa) or reticulated (25 kDa) molecules that prove efficient for gene transfer in vitro and in vivo. Besides extensive applications of unsubstituted PEI, glycosylated-PEI derivatives were proposed and reported to enhance gene transfer efficiency through decreased size and aggregation of PEI/DNA complexes. Galactosylated-PEI derivatives have been reported to enhance interactions with cell membranes through carbohydrate-binding protein recognition and specifically target PEI/DNA complexes toward biological systems that express galectins. More recently, glucosylated PEI derivatives have been shown to yield higher and longer-lasting transgene expression than unsubstituted-PEI in human head and neck carcinoma tumor cells. In the present paper, a review of in vitro and in vivo properties of PEI-mediated gene transfer experiments is presented. (c) 2002 Prous Science. All rights reserved.

Journal Article↗