Baby steps: new work shows the promise, and pitfalls, of embryonic stem-cell research.
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Cloning, Organism↗
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Results for “Advanced Cell Technology Inc.”
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Old MacDonald had an embryo pharm, E, I, E, I, Oh?
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Cloning, Organism↗
Stem cells without embryo loss.
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Advisory Committees↗
New questions emerge over stem-cell research claims.
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Animals↗
Tracking oligodendrocytes during development and regeneration.
Over the past decade, advances in strategies to tag cells have opened new avenues for examining the development of myelin-forming glial cells and for monitoring transplanted cells in animal models of myelin insufficiency. The strategies for labelling glial cells have encompassed a range of genetic modifications as well as methods for directly attaching labels to cells. Genetically modified oligodendrocytes have been engineered to express enzymatic (e.g., beta-galactosidase, alkaline phosphatase), naturally fluorescent (e.g., green fluorescent protein), and antibiotic resistance (e.g., neomycin, zeomycin) reporters. Genes have been introduced in vivo and in vitro with viral or plasmid vectors to somatically label glial cells. To generate germ-line transmission of tagged oligodendrocytes, transgenic mice have been created both by direct injection into mouse fertilized eggs and by "knock-in" of reporters targetted to myelin gene loci in embryonic stem cells. Each experimental approach has advantages and limitations that need to be considered for individual applications. The availability of tagged glial cells has expanded our basic understanding of how oligodendrocytes are specified from stem cells and should continue to fill in the gaps in our understanding of how oligodendrocytes differentiate, myelinate, and maintain their myelin sheaths. Moreover, the ability to select oligodendrocytes by virtue of their acquired antibiotic resistance has provided an important new tool for isolating and purifying oligodendrocytes. Tagged glial cells have also been invaluable in evaluating cell transplant therapies in the nervous system. The tracking technologies that have driven these advances in glial cell biology are continuing to evolve and present new opportunities for examining oligodendrocytes in living systems. Microsc. Res. Tech. 52:766-777, 2001. Published 2001 Wiley-Liss, Inc.
Animals↗
Breast cancer: new technologies for risk assessment and diagnosis.
In the US, one in every eight women will develop breast cancer in her lifetime. Despite the advances made in treating breast cancer, the causal mechanisms underlying this disease have yet to be fully elucidated; 85% of breast cancer cases occur sporadically without any known genetic mutation. Too little is known about the pathogenesis of breast cancer for primary prevention to be feasible in the near- to mid-term. Secondary prevention through screening offers an alternative that has been widely adopted. For decades, breast self-examination has been touted as a technique for the early identification of breast cancer. However, it has been recently suggested that this technique is a waste of time and resources for both doctors and patients. Mammography finds breast cancer earlier than breast self-examination, and will reduce the risk of death from breast cancer by approximately 30% in women over 50 years old. Mammography is limited in that cancer, like breast tissue, appears white on the x-ray; therefore lesions may be difficult to detect in women with very dense breasts, and a tumor may not cast a significant shadow until it is quite large. Some cancers are so aggressive that they can spread quickly, before routine screening can detect them. Despite these limitations, mammography is still viewed as the best tool currently available for screening and early diagnosis. Improved methods to detect and diagnose breast cancer early, when it is most curable, are required if a significant impact on morbidity and mortality from breast cancer is to be made. Various new and innovative technologies are being investigated for improving the early detection and diagnosis of breast cancer. About 85% of breast cancers begin in the milk ductal system of the breast. As cancer develops in the breast, abnormalities occur, including atypical hyperplasia, ductal carcinoma in situ, and invasive breast carcinoma. Thus, the early screening of ductal cells can provide a parallel benefit to the 'Pap' smear, which is used virtually universally to identify the abnormal cells that can lead to cervical cancer. Two technologies to monitor for atypical ductal epithelial cells are Cytyc Corporation's FirstCyte Ductal Lavage system and Nastech Pharmaceutical Company's Mammary Aspiration Cytology Test. Matritech, Inc. is searching for biomarkers linked to breast cancer. Researchers at Matritech have detected the presence of nuclear matrix protein (NMP) in the blood of women at the early stage of breast cancer, which is absent in the blood of healthy women, as well as those with fibroadenoma, a benign breast disease. NMP66 has been selected as a marker for further development and clinical trials of a test for use in the detection and monitoring of women with, or at risk for, breast cancer have been initiated. Technologies developed by the US Department of Defense are under investigation as breast cancer screening. Advanced Image Enhancement, Inc. has licensed naval sonar technology for digital image enhancement of mammograms. New thermography applications are also being investigated in two separate projects sponsored by the US Department of Defense using military thermal surveillance tools adapted for cancer detection. Both are enhancements of older thermal imaging technology based on the principle that heat equates to unwanted activity, in the case of breast cancer, abnormal cell proliferation.
BRCA1 Protein↗
Photodynamic therapy and cancer of the esophagus.
Esophageal carcinoma usually is diagnosed at an advanced, incurable stage. In patients with good operative risk, surgery is still considered the ideal treatment. Patients with coexisting major medical conditions in whom resective surgery is precluded may benefit from several therapeutic options, including photodynamic therapy (PDT) with porfimer sodium (Photofrin; manufactured by Lederle Parenterals, Carolina, Puerto Rico, under license from Quadra Logic Technologies, Inc, Vancouver, British Columbia, Canada), dilation, thermal destruction, Nd:YAG laser ablation, injection therapy, and placement of prosthetic tubes. Photodynamic therapy with porfimer sodium is thought to have a direct toxic effect on malignant cells via the production of singlet oxygen, which damages the microvasculature of the tumor and renders it ischemic. The 630 nm wavelength used for clinical PDT exhibits the greatest relative degree of light penetration into tissue, with corresponding activation of retained photosensitizer. The efficacy of PDT with porfimer sodium is closely related to stage of disease. It should be emphasized that PDT has been shown to be potentially curative in patients with early, noninvasive tumors of both squamous and glandular (adenocarcinoma) histologies. Eighty-three patients with esophageal carcinoma were treated using PDT. At presentation, 60% of patients had recurrence following previous radiotherapy or chemotherapy. Patients with less advanced disease had a better response to PDT with regard to relief of dysphagia and prolongation of survival. Photodynamic therapy was found to be more useful than Nd:YAG laser therapy for high, upper third lesions, especially circumferential ones. For tumors larger than 8 cm, PDT was twice as effective as Nd:YAG laser therapy in establishing prolonged lumen patency, especially for adenocarcinomas. Photodynamic therapy appears to have the added advantages of fewer treatments and less pain. The role of PDT in gastrointestinal malignancies continues to evolve.
Adenocarcinoma↗
Inhibitors of tryptase for the treatment of mast cell-mediated diseases.
Human tryptase is a structurally unique and mast cell specific trypsin-like serine protease. Recent biological and immunological investigations have implicated tryptase as a mediator in the pathology of numerous allergic and inflammatory conditions including rhinitis, conjunctivitis, and most notably asthma. A growing body of data further implicates tryptase in certain gastrointestinal, dermatological, and cardiovascular disorders as well. The recent availability of potent, and selective tryptase inhibitors, though, has facilitated the validation of this protease as an important therapeutic target as well. Herein, we describe the design and potency of four classes of selective tryptase inhibitors, of which the first three types are synthetic and the fourth is natural in origin: 1) peptidic inhibitors (e.g., APC-366), 2) dibasic inhibitors (i.e., pentamidine-like), 3) Zn(2+)-mediated inhibitors (i.e., BABIM-like), and 4) heparin antagonists (e.g., lactoferrin). These inhibitors have been tested in the airways and skin of allergic sheep. Aerosol administration of tryptase inhibitors from each structural class 30 minutes before, and 4 hours and 24 hours after allergen challenge, abolishes late phase bronchoconstriction and airway hyperresponsiveness in a dose-dependent manner. Moreover, intradermal injection of APC-366 blocks the cutaneous response to antigen. These studies provide the essential proof-of-concept for the further pursuit of tryptase inhibitors for the treatment of asthma, and perhaps other allergic diseases. Results from clinical studies with the first generation tryptase inhibitor APC-366, currently in phase II trials for the treatment of asthma, provide additional support for a pathological role for tryptase in this disease. Notable advances in the area of tryptase inhibitor design at Axys Pharmaceuticals, Inc. include a novel, zinc-mediated, serine protease inhibitor technology (described herein), and the discovery of a unique class of extremely potent and selective dibasic tryptase inhibitors. Independently, an X-ray crystal structure of active tryptase tetramer complexed with 4-amidinophenyl pyruvic acid has been reported. It is anticipated that these discoveries will further accelerate the design of structurally novel tryptase inhibitors as well as the development of new drugs for the treatment of mast cell tryptase-mediated disorders.
Animals↗
Tissue engineering: challenges and opportunities.
This article reviews the key developments in the tissue engineering field over the past several years. The issues related to the development of the components of tissue-engineered products including cells, biomaterials, and biomolecules, and their integration into safe and effective products are presented. Moreover, the article outlines the challenges to the commercialization of tissue-engineered products, and highlights the ongoing efforts by the American Society for Testing and Materials (ASTM) in developing standards for tissue-engineered medical products. Furthermore, funding opportunities at the Advanced Technology Program at NIST are presented. Published 2000 John Wiley & Sons, Inc.
Animals↗
Engineered antibodies accelerating drug discovery and development.
This meeting, organized by the Strategic Research Institute, reviewed advances in both engineering technologies and clinical development of antibody products. A panel of speakers, mainly from the biotechnology and pharmaceutical industries, covered several important issues in the development of antibody therapeutics, including new display technologies, human antibody generation, high-level expression of antibodies in both mammalian cells and in transgenic plants, and the latest data from ongoing clinical trials of antibody products. In the case of human antibody generation, Abgenix Inc's XenoMax technology combines the powers of the transgenic XenoMouse and in vitro B cell culture and selection to enable the robust identification of antibodies with rare properties and very high affinity. MAbstract from Crucell NV provides a unique approach to the identification of human antibodies directed against tumor-specific glycosylation variants and activation epitopes of otherwise normal cellular molecules. Regarding antibody production, the use of transgenic plants is gaining more interest among biopharmaceutical industrials. Promising results were also reported on several antibody-based therapeutic, including antibody-drug conjugates and prodrugs.
Journal Article↗
Discovery of novel tumor markers of pancreatic cancer using global gene expression technology.
Despite several advances in our basic understanding and in the clinical management of pancreatic cancer, virtually all patients who will be diagnosed with pancreatic cancer will die from this disease. The high mortality of pancreatic cancer is predominantly because of diagnosis at an advanced stage of disease and a lack of effective treatments. We used the Gene Logic Inc. BioExpress platform and Affymetrix GeneChip arrays to identify genes differentially expressed in pancreatic cancer. cDNA was prepared from samples of normal pancreas (n = 11), normal gastrointestinal mucosa (n = 22), resected pancreas cancer tissues (n = 14), and pancreas cancer cell lines (n = 8), and was hybridized to the complete Affymetrix Human Genome U95 GeneChip set (arrays U95 A, B, C, D, and E) for simultaneous analysis of 60,000 cDNA fragments, with 12,000 fragments covering full-length genes and 48,000 fragments covering expressed sequence tags (ESTs). Genes expressed at levels at least fivefold greater in the pancreatic cancers ascompared to normal tissues were identified. Serial analysis of gene expression (SAGE) libraries (http://www.ncbi.nlm.nih.gov/SAGE/) of two normal pancreatic ductal cell cultures (HX and H126) were used to exclude genes expressed in the normal ducts (more than five tags per library). Differential expression of selected candidate genes was validated by immunohistochemical analysis (n = 3), by in situ hybridization (n = 1), and by reverse transcriptase-polymerase chain reaction (n = 8). One hundred eighty fragments were identified as having fivefold or greater expression levels in pancreas cancer specimens as compared to normal tissue, of which 124 corresponded to known genes and 56 to ESTs. Of these 124 fragments, 10 genes were represented by two or more fragments, resulting in 107 known genes identified as differentially expressed in pancreatic cancer. An additional 10 genes were expressed in the SAGE libraries of normal pancreatic duct epithelium, and were excluded from further analysis. A literature search indicated that 28 of the remaining 97 genes have been reported in association with pancreatic cancer, validating this approach. The remaining 69 genes have not been implicated in pancreatic cancer before, and have immediate potential as novel therapeutic targets and tumor markers of pancreatic cancer.
Biomarkers, Tumor↗
Technology evaluation: CN-706, Calydon Inc.
CN-706, an engineered adenovirus containing the prostate tissue-specific enhancer (PSE) gene is under development by Calydon as a potential treatment for prostate cancer. The company is collaborating with the Johns Hopkins Hospital, which has agreed to sponsor clinical trials [274956]. Phase I trials in patients with advanced and recurring prostate cancer began during 1998 at the Johns Hopkins Brady Urological Institute and the Oncology Center [283946], [296857], and the results of phase I/II trials were reported in 2000 [386879]. The US Patent Office issued three patents in October 1998 [301251] related to Calydon's technology for engineering viruses to replicate and kill prostate cancer cells [US-05648478], [US-05698443], [US-05783435]. In June 1999, Calydon was issued two further patents [US-05871726], [US-05830686], [327511].
Adenoviridae↗
Technology evaluation: GEM-92, Hybridon Inc.
Hybridon is developing GEM-92, a second generation, orally administered antisense oligonucleotide directed against the gag gene in HIV-1 mRNA, as a potential treatment for HIV-1 infection and AIDS 11973841. It is a follow-up compound to GEM-91, which was discontinued due to dose-limiting toxicities [256660]. GEM-92 is undergoing phase I trials in the UK, in approximately 13 healthy volunteers. Hybridon intends to administer a single oral dose at one of three dose levels, while a fourth group will receive a single intravenous dose, in order to determine differences between oral and intravenous administration [263095]. GEM-92 has demonstrated significant inhibition of HIV-1 replication in various cell culture systems, and increased stability in comparison with GEM-91 [219621]. Hybridon has been issued two US patents; US-05652355 and US-05652356, claiming chemically advanced mixed backbone oligonucleotides [257135].
Animals↗
[A model for clinical study based on genome science--trials in disorders of the immune system and allergies].
Disorders of the immune system, such as allergies, have multi-factorial etiologies that include both genetic and environmental components. The recent advances in genome science have facilitated two strategies for studying the genetic basis of disease: (1) systematic analysis of gene expression profiles and (2) comprehensive analysis of gene variations, such as polymorphisms. Here, we describe a unique research institute, Genox Research Inc., that can relate the clinical profile of a patient to genotyping and molecular profiling. Systematic gene expression analyses using differential display have been performed to explore genes related to allergy, and revealed 93 differentially expressed candidate genes in T-cells. Also, a single nucleotide polymorphism(SNP) analysis project has been designed to mine disease-related and/or drug-response-related genes involved in allergic disorders using biochip technologies. As exemplified above, clinical studies based on these applications of genome science would be of considerable value in clarifying our understanding of multi-gene disorders.
Gene Expression Profiling↗
European experience in the treatment of hyperuricemia.
The nonrecombinant form of urate oxidase has been routinely used in France since 1975 as standard practice in the initial management of non-Hodgkin's lymphoma (NHL) and acute lymphoblastic leukemia (ALL), and for prevention of tumor lysis syndrome (TLS). A retrospective study was performed to evaluate the frequency of metabolic complications and dialysis in 410 patients with B-cell stage III and IV NHL and L-3 ALL treated in France according to the LMB89 protocol, and to compare these results to those of other series of patients treated without urate oxidase. Of the 57 patients treated at Institut Gustave-Roussy, only five had metabolic complications occurring in the first cycle of chemotherapy. Two patients (3.5%) underwent dialysis: one because of oliguria, the second for preventive reasons. In all the other cases, metabolic problems were successfully resolved or prevented, using nonrecombinant urate oxidase (Uricozyme, Sanofi-Sythélabo, Inc, Paris, France) in combination with hyperhydration. Nonrecombinant urate oxidase is generally well tolerated. However, allergic reactions may occur, with rates varying from 0% to 4.5%. In addition, the extraction technology used to produce the product is limited by a low yield. A recombinant form of urate oxidase (rasburicase) was therefore developed. European clinical development results indicate that this agent produces a sharp and consistent decrease in uric acid levels in patients undergoing cytoreductive therapy. Additionally, there is a very low incidence of anaphylaxis. Studies have demonstrated the efficacy of urate oxidase in lowering uric acid levels, preventing hyperuricemia after the initiation of cytoreductive therapy, and preserving renal function in patients with B-cell advanced stage NHL and ALL.
Adolescent↗
Sex-Sorting mammalian sperm: concept to application in animals.
Sperm sexing can be used to produce sexed offspring with 85%-95% accuracy (Amann, 1999; Johnson and Seidel, 1999; Seidel et al 1999a). On September 1, 2000, the sale of sexed bovine sperm commented in the United Kingdom. It will be interesting to see to what degree sexed sperm penetrate the semen market. This verified sexed product sets the stage for commercialization around the world in major animal producing countries. This commercialization of sexed sperm occurred nearly 20 years after technology for accurately determining the proportion of X and Y sperm in semen was first developed at Lawrence Livermore National Laboratory. It came about due to advances in both the hardware and the software componenets of computer science, biophysic, cell biology and applied reproductive physiology plus efforts of innovative scientist. Many individuals have contributed in making semen sexing in animals a commercial reality since the research team of Bart Gledhill, Dan Pinkel, Duane Garner, Susan Lake, and Larry Johnson began following up on the first flow cytometric studies on human sperm by Friedrich Otto, Wolfgang Göhde, and Marvin Meistrich. There was also major input from personnel at USDA Beltsville Agricultural Research Center as well as scientists at Cambridge University, Atlantic Breeders Cooperative, Colorado State University and XY Inc. These include Chuck Allen, Rupert Amann, David Cran, Patrick Doyle, Mike Evans, Lisa Herickhoff, Mervyn Jacobson, Kehuan Lu, Chris Polge, Wim Rens, John Schenk, George Seidel, Glenn Welch, and many others.
Animals↗
Technology evaluation: VEGF165 gene therapy, Valentis Inc.
Valentis Inc, formerly GeneMedicine, is developing a vascular endothelial growth factor (VEGF165) non-viral gene therapy using its proprietary PINC polymer for plasmid condensation. Two physician-initiated phase II angioplasty trials are ongoing, one for treating peripheral vascular disease and one for treating coronary artery disease [281714], [347153]. In February 2000, the trials were expected to be completed in the fourth quarter of 2000 [356225]; however, in October 2000, it was reported that the trial for peripheral vascular disease would be completed in the first quarter of 2001 [385232]. In March 2000, Valentis initiated a trial incorporating Valentis's DOTMA-based cationic lipid gene delivery system and the VEGF165 gene with Eurogene's local collar-reservoir delivery device. The trial is designed to demonstrate that the VEGF165 gene, delivered locally to the outside surface of a blood vessel, will transfect and express in the smooth muscle cells of the vessel wall [360683]. In March 1999, Valentis was awarded with a Phase II SBIR grant of $686,260. The aim of grant was to advance the development of non-viral gene therapies for ischemia. Specifically, Valentis intended to select an optimal promoter to be used with the VEGF expression plasmid. Valentis also intended to evaluate the gene therapy system in a rabbit ischemia model and complete the necessary preclinical studies for submission of an IND [318137].
Angioplasty↗