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PubMed1992

Evaluation of methods for detecting ecological effects from genetically engineered microorganisms and microbial pest control agents in terrestrial systems.

This report summarizes and evaluates research from several laboratories that deals with the detection of ecological effects induced through exposure of microbes or plants to genetically engineered microorganisms (GEMs) and microbial pest control agents (MPCAs). Some 27 potential endpoints for measuring effects have been studied. Perturbations induced by GEMs have been detected in about one-half of these endpoints. Detectable effects have been recorded for over half of the 16 species of bacteria and fungi studied. The effects caused by GEMs and MPCAs include inhibition of beneficial mycorrhizal fungi growing on Douglas fir seedling roots, depression in plant root and shoot growth, inhibition of predatory soil protozoa, accumulation of a toxic metabolite during biodegradation that inhibits soil fungi, increased microbial community respiration due to rapid lignin breakdown in soil, and the displacement of a broad group of gram-negative bacteria that inhabit the root surface of cereal crops. These effects were usually, but not always, of short duration. However, some of the changes were irreversible during the observation time of days, weeks, or in one case, months.

Journal Article↗
PubMed2002

Genetically engineered mouse models of neurodegenerative diseases.

Recent research has significantly advanced our understanding of the molecular mechanisms of neurodegenerative diseases, including Alzheimer's disease (AD) and motor neuron disease. Here we emphasize the use of genetically engineered mouse models that are instrumental for understanding why AD is a neuronal disease, and for validating attractive therapeutic targets. In motor neuron diseases, Cu/Zn superoxide dismutase and survival motor neuron mouse models are useful in testing disease mechanisms and therapeutic strategies for amyotrophic lateral sclerosis (ALS) and spinal motor atrophy, respectively, but the mechanisms that account for selective motor neuron loss remain uncertain. We anticipate that, in the future, therapies based on understanding disease mechanisms will be identified and tested in mouse model systems.

Alzheimer Disease↗
PubMed1996

Anaerobic bacteria as a delivery system for cancer gene therapy: in vitro activation of 5-fluorocytosine by genetically engineered clostridia.

Certain species of anaerobic bacteria have been shown to localise and germinate specifically in the hypoxic regions of tumours, resulting in tumour lysis. We propose an innovative approach to cancer gene therapy in which genetically engineered anaerobic bacteria of the genus Clostridium are used to achieve tumour-specific gene delivery. Our strategy involves enzyme/prodrug therapy, in which the Escherichia coli enzyme cytosine deaminase is used to convert the non-toxic prodrug 5-fluorocytosine to the active chemotherapeutic agent 5-fluorouracil. The E. coli gene encoding cytosine deaminase has been cloned into a clostridial expression vector and transformed into Clostridium beijerinckii, resulting in constitutive expression of cytosine deaminase and significant levels of active enzyme in the bacterial medium. When added to an in vitro clonogenic survival assay, supernatant from clostridia expressing cytosine deaminase increased the sensitivity of murine EMT6 carcinoma cells to 5-fluorocytosine approximately 500-fold. This high level of prodrug activation, combined with the specificity of clostridia for hypoxic regions of tumours, indicates a potential use in cancer gene therapy.

Animals↗
PubMed1998

[Application of genetically engineered animals in pharmacology: the use of green fluorescent protein for selective production of transgenic animals].

Transgenic animals are a very important tool not only for basic science but also for the pharmaceutical industry. The use of genetically engineered farm animals are suitable as a disease model. Production of a therapeutic protein such as human clotting factors by transgenic animals will reduce the risk of infection with human immunodeficiency virus and hepatitis virus. The efficiency of transgenic animal production, however, has been low and thus limited its application. We improved the efficiency using a green fluorescent protein (GFP) as a marker of gene integration. Using this method, we obtained 12 fetuses, and Southern blot analysis showed eight of them were transgenic, indicating transgenic embryos were successfully selected at the preimplantation stage. We also observed similar GFP expression in rat and bovine blastocysts. Application of this GFP selection method should improve the efficiency of transgenic livestock production.

Animals↗
PubMed2002

Genetically engineered intracellular single-chain antibodies in gene therapy.

The delineation of the molecular basis of cancer allows for the possibility of specific intervention at the molecular level for therapeutic purposes. To a large extent, the genetic lesions associated with malignant transformation and progression are being identified. Thus, not only in the context of inherited genetic diseases, but also for many acquired disorders, characteristic aberrancies of patterns of gene expression may be precisely defined. It is therefore clear that elucidation of the genetic basis of inherited and acquired diseases has rendered gene therapy both a novel and rational approach for these disorders. To this end, three main strategies have been developed: mutation compensation, molecular chemotherapy, and genetic immunopotentiation. Mutation compensation relies on strategies to ablate activated oncogenes at the level of DNA (triplex), messenger RNA (antisense or ribozyme), or protein (intracellular single-chain antibodies), and augment tumor suppressor gene expression. This article will review in detail practical procedures to generate a single-chain intracellular antibody (scFv). We will emphasize in this article the different steps in our protocol that we have employed to develop scFvs to a variety of target proteins.

Antibodies↗
PubMed1989

Efficient expression of genetically engineered hepatitis B virus surface antigen P31 proteins in yeast.

We have constructed plasmids that express modified hepatitis B virus surface antigen (HBsAg) P31-coding genes (M-P31c, d, e, f, and i) having various genetically engineered pre-S2 regions. The plasmids contain the GAPDH (gene coding for glyceraldehyde-3-phosphate dehydrogenase) promoter and the PGK (gene coding for 3-phosphoglycerate kinase) terminator, both isolated from sake brewing yeast, Saccharomyces cerevisiae Kyokai III. Expression levels of the modified HBsAg P31 proteins in yeast are greatly increased from 0.4% to 11.7% of total cell protein. However, the specific mRNAs are expressed at equal levels and the degradation rates of the modified P31 proteins do not vary significantly. Therefore, we considered that different expression levels of the modified P31 proteins are attributed to the changes of the post-translational efficiency. And it was suggested that the conformational stability of the N-terminal peptide (Met-1-Phe-46) in the endoplasmic reticulum membrane determines the expression level of modified P31 proteins.

Amino Acid Sequence↗
PubMed2005

Genetically engineered bacteriocins and their potential as the next generation of antimicrobials.

The discovery of penicillin by Fleming in 1928 was an historical milestone in the fight against infectious disease. Over the following fifty years, pharmaceutical companies discovered and developed over 100 antibiotics effective against a wide range of human pathogens. More recently, the dramatic rise in antibiotic-resistant pathogens has stimulated renewed efforts to identify, develop or redesign antibiotics active against these multi-resistant bacteria. This review focuses on such efforts directed at one large and highly diverse family of toxins, the bacteriocins, which hold great promise as the next generation of antimicrobials. The majority of bacteriocins differ from traditional antibiotics in one critical way: they have a relatively narrow killing spectrum and are, therefore, toxic only to bacteria closely related to the producing strain. Accordingly, they can be considered "designers drugs" that target specific bacterial pathogens. In this review we focus on recent attempts to generate custom designed bacteriocins using genetic engineering techniques. These efforts illustrate the potential of genetically-modified bacteriocins to solve some of the most challenging problems in disease control.

Animals↗
PubMed1999

Interleukin 2 gene therapy of colorectal carcinoma with autologous irradiated tumor cells and genetically engineered fibroblasts: a Phase I study.

The purpose of this study was to determine the safety, toxicity, and antitumor immune response following S.C. immunizations with a mixture of irradiated, autologous tumor cells and autologous fibroblasts that were genetically modified to express the gene for interleukin 2 (IL-2) in patients with colorectal carcinoma. Ten patients were treated with a fixed dose of tumor cells (10(7)) and escalating doses of fibroblasts secreting IL-2 (per 24 h): 100 units (three patients), 200 units (three patients), 400 units (three patients), and 800 units (one patient). Pre- and posttreatment peripheral blood mononuclear cells were evaluated for evidence of antitumor immune responses. Fatigue and/or flu-like symptoms were experienced by seven patients and delayed-type hypersensitivity-like skin reactions were observed at the sites of the second or subsequent vaccinations in five patients. Low frequencies of tumor cytotoxic T-cell precursors (range, 1/190,000-1/1,320,000 peripheral blood mononuclear cells) were detected prior to therapy in four of seven patients. There was a 5-fold increase following treatment in the frequency of tumor cytotoxic T-cell precursors in two of six evaluable patients. Some patients with colorectal cancer have low frequencies of tumor cytotoxic T-cell precursors that may be increased by this well-tolerated form of IL-2 gene therapy, which warrants continued clinical evaluation.

Cancer Vaccines↗