Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684275 (haemophilia)
 10,958 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ER-Golgi intermediate compartment (ERGIC) marker ERGIC-53 is a mannose-specific membrane lectin operating as a cargo receptor for the transport of glycoproteins from the ER to the ERGIC. Lack of functional ERGIC-53 leads to a selective defect in secretion of glycoproteins in cultured cells and to hemophilia in humans. Beyond its interest as a transport receptor, ERGIC-53 is an attractive probe for studying numerous aspects of protein trafficking in the secretory pathway, including traffic routes, mechanisms of anterograde and retrograde traffic, retention of proteins in the ER, and the function of the ERGIC. Understanding these fundamental processes of cell biology will be crucial for the elucidation and treatment of many inherited and acquired diseases, such as cystic fibrosis, Alzheimer's disease and viral infections.
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PMID:ERGIC-53 and traffic in the secretory pathway. 1065 52

Recombinant adeno-associated viruses (AAV) are promising gene therapy vectors. Whereas AAV serotype 2-mediated gene transfer to muscle has partially replaced factor IX deficiency in hemophilia patients, its ability to mediate gene transfer to the lungs for cystic fibrosis is hindered by lack of apical receptors. However, AAV serotype 5 infects human airway epithelia from the lumenal surface. We found that in contrast to AAV2, the apical membrane of airway epithelia contains abundant high affinity receptors for AAV5. Binding and gene transfer with AAV5 was abolished by genetic or enzymatic removal of sialic acid from the cell surface. Furthermore, binding and gene transfer to airway epithelia was competed by lectins that specifically bind 2,3-linked sialic acid. These observations suggest that 2,3-linked sialic acid is either a receptor for AAV5 or it is a necessary component of a receptor complex. Further elucidation of the receptor for this virus should enhance understanding of parvovirus biology and expand the therapeutic targets for AAV vectors.
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PMID:Binding of adeno-associated virus type 5 to 2,3-linked sialic acid is required for gene transfer. 1126 13

Gene therapy was initially conceived of as a means of replacing defective genes in monogenic disorders such as cystic fibrosis or hemophilia, but has rapidly progressed into areas of medicine that involve a wide range of diseases including cancer, neurodegenerative disorders and autoimmunity. Elucidation of some of the cellular and molecular mechanisms implicated in the pathogenesis of joint inflammation and cartilage and bone destruction in inflammatory joint diseases such as rheumatoid arthritis (RA) have revealed novel targets for gene therapy. Strategies include the inhibition of pro-inflammatory cytokines, blockade of cartilage-degrading enzymes, inhibition of synovial cell activation or apoptosis of synovial cells, and manipulation of the Th1-Th2 cytokine balance. Both viral and non-viral gene transfer vector systems have been used to deliver therapeutic genes systemically or directly to arthritic joints by ex vivo as well as in vivo administration. Animal models of RA have been essential not only for better understanding the mechanisms of RA but also in serving as basic experimental tools to evaluate candidate gene products with anti-arthritic properties and develop therapeutic strategies.
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PMID:Gene therapy for rheumatoid arthritis. 1152 60

Implanted vascular access devices (ports) play a major role in the management of children with cystic fibrosis (CF) and many haematological conditions. With the expanding use of ports, new and more frequent complications are being encountered. To retrospectively review the complications associated with ports, the case notes of all patients who underwent insertion of a port between 1997 and 2000 were analysed. Details of the underlying disorder, type of vascular device, nature of use, and complications were recorded; 55 ports were inserted in 41 patients (a second port was required in 12, a third port in 2) during this period. Their underlying diagnoses were CF (11), haemophilia (4), haemolytic anaemias (2), immunological disorders (6), solid neoplasms (8), and leukaemia (10). Thirteen ports (24%) were removed and replaced for various complications: infection (2), blockage (4), leak (2), dislodgement (2), and malposition (3). Including four port-related problems managed conservatively (3 access problems managed by change in access technique; 1 blockage managed by urokinase), the over all complication rate was 31%. Ports thus have a high complication rate with long-term use. Selecting the right port system, proper installation of the port chamber, and efficient handling and maintenance by trained staff could prevent the vast majority of port-related complications.
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PMID:Implanted vascular access devices (ports) in children: complications and their prevention. 1272 47

The structure of the adeno-associated virus (AAV-2) has been determined to 3-A resolution by x-ray crystallography. AAV is being developed as a vector for gene therapy to treat diseases including hemophilia, cancer, and cystic fibrosis. As in the distantly related autonomous parvoviruses, the capsid protein has a beta-barrel fold, but long loops between the beta-strands share little structural homology with other parvoviruses, leading to unique surface features. Most prominent are groups of threefold-related peaks, each an intimate association of loops from two neighboring subunits. Mutations affecting cell entry and receptor binding are clustered near the positively charged side of each peak, implicating the region in attachment to the cellular receptor, heparan sulfate proteoglycan. Amino acids involved in antibody binding are in the same general vicinity. The structure will guide rational engineering of vector capsids to tailor cellular targeting and to avoid immediate neutralization by an immune system sensitized by prior exposure to AAV.
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PMID:The atomic structure of adeno-associated virus (AAV-2), a vector for human gene therapy. 1213 30

We have applied a new method of genetic analysis, called 'minisequencing', to preimplantation genetic diagnosis (PGD) of monogenic disorders from single cells. This method involves computer-assisted mutation analysis, which allows exact base identity determination and computer-assisted visualization of the specific mutation(s), and thus facilitates data interpretation and management. Sequencing of the entire PCR product is unnecessary, yet the same qualitative characteristics of sequence analysis are maintained. The main benefit of the minisequencing strategy is the use of a mutation analysis protocol based on a common procedure, irrespective of the mutations involved. To evaluate the reliability of this method for subsequent application to PGD, we analysed PCR products from 887 blastomeres including 55 PGD cases of different genetic diseases, such as cystic fibrosis, beta-thalassaemia, sickle cell anaemia, haemophilia A, retinoblastoma, and spinal muscular atrophy. Minisequencing was found to be a useful technique in PGD analysis, due to its elevated sensitivity, automation, and easy data interpretation. The method was also efficient, providing interpretable results in 96.5% (856/887) of the blastomeres tested. Fifteen clinical pregnancies resulted from these PGD cases; conventional prenatal diagnosis confirmed all the PGD results, and 10 healthy babies have already been born. Its applicability to PGD could be helpful, particularly in cases in which the mutation(s) involved are difficult to assess by restriction analysis or other commonly used methods.
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PMID:The minisequencing method: an alternative strategy for preimplantation genetic diagnosis of single gene disorders. 1280 47

Pulmonary gene therapy offers the hope of treatment for conditions such as cystic fibrosis, lung cancer, pulmonary fibrosis and acute respiratory distress syndrome for which current therapy is inadequate. Although initial clinical trials in cystic fibrosis and non-small cell lung cancer have shown promise the results have not been as good as might have been anticipated. However, clinical improvement has been demonstrated in conditions such as haemophilia [82], cardiovascular disease [83], head and neck cancer [84] and X-linked severe combined immunodeficiency disease [85]. The lack of success of pulmonary gene therapy is due, in part on the physical barriers to transfection perfected by the lung to prevent toxicity from inhaled particles, and partly due to the poor transfection efficiency of non-viral systems, and the immunogenicity of viral systems, of gene transfer. The LID vector goes some way to addressing the problems associated with current gene delivery strategies. With continued improvements in the properties of both viral and non-viral gene delivery systems leading to improved transfection efficiency with reduced toxicity, as well as the development of strategies aimed at reducing the physical barriers to pulmonary transfection, and targeting gene delivery systems to the site of injury, it is likely that pulmonary gene therapy will be used successfully to ameliorate a number of devastating pulmonary conditions.
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PMID:Pulmonary gene therapy. Realistic hope for the future, or false dawn in the promised land? 1453 78

Gene therapy is envisioned as a potentially definitive treatment for a variety of diseases that have a genetic etiology. We reviewed trials of clinical gene therapy for nonmalignant, single-gene, and multifactorial disorders and infectious diseases, and found limited evidence suggesting that gene therapy may benefit patients who have severe, combined, immunodeficiency disorder; cystic fibrosis; coronary artery disease or peripheral arterial disease; or hemophilia. Effective gene therapy requires the targeted transfer of exogenous genetic material into human cells and the subsequent regulated expression of the corresponding gene product. Because no phase 3 randomized controlled trials have been completed that fulfill these criteria, it is difficult to correlate signs of clinical benefit with the administration of gene therapy in any disease. Additional clinical and basic research is needed to determine the future role of gene therapy.
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PMID:Clinical gene therapy for nonmalignant disease. 1459 36

The first International Conference on Clinical Gene Therapy focused primarily on gene therapy for cardiovascular disorders, genetic diseases (hemophilia, cystic fibrosis) and cancer, with particular emphasis on clinical trials and advanced preclinical studies. Recent improvements in vector technologies led to the first demonstration that gene therapy could cure a disease in a clinically relevant animal model of hemophilia. This significant progress at the preclinical level, using both viral and non-viral vectors, paved the way for phase I clinical trials in patients suffering from hemophilia A. The first report on hemophilia A gene therapy using a non-viral ex vivo approach was encouraging and revealed modest improvements in clinical endpoints. The status of clinical gene therapy for the treatment of peripheral limb and myocardial ischemia by therapeutic angiogenesis was highlighted as showing an apparent increase in collateral development and reduced limb or myocardial ischemia in some patients. Gene therapy for cystic fibrosis turned out to be a much tougher nut to crack than initially assumed, and the hopes for, and hurdles faced by, gene therapy approaches for this disease were discussed. Phase III clinical trials using retroviral-based suicide gene therapy for cancer revealed no significant therapeutic benefit in patients suffering from glioblastoma multiforme. Nevertheless, new and promising approaches for cancer gene therapy are being developed that rely on the use of targetable vectors and conditionally replicating vectors that replicate specifically in cancer cells; this may overcome some of the bottlenecks of cancer gene therapy by improving therapeutic efficacy. Although few diseases have been treated effectively by gene therapy so far, the stage appears set for new and significant advances in clinical trials.
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PMID:Clinical gene therapy - first international conference. 24-26 January 2002, Groningen, the Netherlands. 1556 27

The field of gene therapy, delivering genes to directly treat diseases, has had a remarkable year. This is no more evident than in the scope of the third annual meeting of the American Society of Gene Therapy (ASGT). Clear progress has been made in both ex vivo clinical protocols and in vivo administration. The meeting covered every major method of gene delivery, from injection of naked DNA to advanced synthetic gene delivery systems, as well as the major viral-based vectors. The optimism of the society was tempered, however, by the much-publicized death of a patient in a clinical trial at the University of Pennsylvania last year. There was a correspondingly high regulatory presence at the meeting, with several presentations by representatives of the US FDA and National Institutes of Health (NIH). Major clinical advances in gene therapy have been in genetic diseases, including hemophilia, severe combined immunodeficiency, and cystic fibrosis. Therapies are in later-stage clinical trials, and evidence of efficacy has been demonstrated, most notably by the apparent cure of SCID-affected children in Paris by ex vivo gene therapy with cytokine receptor subunit genes. Cancer gene therapy is also making significant headway, with many products entering phase II and III trials. Basic technology development is proceeding in vector targeting, enhancement of gene transfer efficiency, and regulating expression of therapeutic genes. In addition, basic research demonstrates the promise of new combined modes for treating diseases such as muscular dystrophy, lysosomal storage diseases and cardiovascular disease.
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PMID:American Society of Gene Therapy - Third Annual Meeting. 1604 54


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