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1.
D. Lattuada M. Mazzei R. Meazza A. Nicolin 《International Journal of Clinical & Laboratory Research》1992,21(2-4):296-299
Summary Antisense oligonucleotides and their derivatives have been shown to be specific inhibitors of gene expression. They are considered
a very promising new generation of drugs, potentially useful in most human diseases, including cancers and viral infections.
The elegance of the antisense oligonucleotides lies in their ability to bind, via standard Watson-Crick base pairing, a complementary
region within a target mRNA. Although easily synthesized, therapeutic applications have been restricted by a number of difficulties
including: stability, pharmacokinetic behavior (both a cellular and at systemic level), and the high cost of industrial production.
The object of this review is to briefly describe the major properties of antisense oligonucleotides, the modalities currently
under investigation to circumvent the difficulties in their use, and the up-to-date experimental applications, including findings
from our own laboratory. As very few oligonucleotides need to be synthesized in order to obtain an active compound, compared
with an average of 10000 new standard compounds, prospects are extremely exciting and worthy of maximum attention. 相似文献
2.
Delivery systems for antisense oligonucleotides 总被引:9,自引:0,他引:9
Garcia-Chaumont C Seksek O Grzybowska J Borowski E Bolard J 《Pharmacology & therapeutics》2000,87(2-3):255-277
In vitro, the efficacy of the antisense approach is strongly increased by systems delivering oligodeoxyribonucleotides (ODNs) to cells. Up to now, most of the developed vectors favor ODN entrance by a mechanism based on endocytosis. Such is the case for particulate systems, including liposomes (cationic or non-cationic), cationic polyelectrolytes, and delivery systems targeted to specific receptors. Under these conditions, endosomal compartments may represent a dead end for ODNs. Current research attempts to develop conditions for escaping from these compartments. A new class of vectors acts by passive permeabilization of the plasma membrane. It includes peptides, streptolysin O, and cationic derivatives of polyene antibiotics. In vivo, the interest of a delivery system, up to now, has appeared limited. Development of vectors insensitive to the presence of serum seems to be a prerequisite for future improvements. 相似文献
3.
反义寡核苷酸研究进展 总被引:1,自引:0,他引:1
反义寡核苷酸的研究已进入一个新的阶段 ,有望在抗病毒、抗肿瘤、炎症性疾病方面成为新的药物 ,并且是研究基因功能的一个有用工具。现对反义寡核苷酸的设计、靶位点选择、修饰 ,以及临床等方面的研究进展作一综述 相似文献
4.
D Lattuada M Mazzei R Meazza A Nicolin 《International Journal of Clinical & Laboratory Research》1992,21(4):296-299
Antisense oligonucleotides and their derivatives have been shown to be specific inhibitors of gene expression. They are considered a very promising new generation of drugs, potentially useful in most human diseases, including cancers and viral infections. The elegance of the antisense oligonucleotides lies in their ability to bind, via standard Watson-Crick base pairing, a complementary region within a target mRNA. Although easily synthesized, therapeutic applications have been restricted by a number of difficulties including: stability, pharmacokinetic behavior (both a cellular and at systemic level), and the high cost of industrial production. The object of this review is to briefly describe the major properties of antisense oligonucleotides, the modalities currently under investigation to circumvent the difficulties in their use, and the up-to-date experimental applications, including findings from our own laboratory. As very few oligonucleotides need to be synthesized in order to obtain an active compound, compared with an average of 10,000 new standard compounds, prospects are extremely exciting and worthy of maximum attention. 相似文献
5.
Formulations of antisense oligonucleotides (asODNs) against c-myb or c-myc protooncogenes have been prepared by a new technique that sequesters cationic lipid in the interior of a lipid particle. This technique results in high loading efficiency for the asODNs, small particle size and good stability. When targeted against melanoma cells or neuroblastoma cells via anti-GD(2) coupled at the particle surface, increased cell binding to the cells could be demonstrated. Targeted formulations showed greater inhibition of cell proliferation compared to non-targeted formulations or free drug. Inhibition of cell proliferation was demonstrated to be due to down-regulation of c-myb or c-myc protein expression. The formulations have long-circulation times in vivo, and evaluation for in vivo antitumor activity is currently underway. 相似文献
6.
Brand RM 《Current opinion in molecular therapeutics》2001,3(3):244-248
Antisense oligonucleotides have great potential as therapeutic agents. As a result, a variety of chemistries have been developed to improve the efficacy of these molecules without compromising their specificity. Because the skin is such a large organ with extensive accessibility, it is a natural target for drug delivery. It is, however, an effective barrier, so physical and chemical methods to improve drug penetration have been developed. These enhancement techniques can be combined with modified oligonucleotide chemistries to provide sufficient levels of antisense activity either within the skin or systemically. This review will describe in vitro and in vivo experiments that demonstrate the potential of antisense oligonucleotides to treat both dermal and systemic disorders. 相似文献
7.
Activation of adenylate cyclase by cholera toxin in rat liver homogenates. 总被引:6,自引:0,他引:6
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The effect of cholera toxin on adenylate cyclase from rat liver has been studied in a broken cell preparation. The activation of the enzyme in this in vitro preparation requires the addition of nicotinamide adenine dinucleotide (NAD) to the incubation medium and the presence of cell components other than the membrane-bound adenylate cyclase. Once the activation of the cyclase is produced, the effect persists despite repeated washing or solubilization of the enzyme. The effect can be obtained with concentrations of cholera toxin as low as 0.4 nM after 15 min of incubation at 22 degrees C, and stimulation can be detected after only 5 min of incubation at 37 degrees C. The activation of the enzyme is still apparent after at least 2 h at 0 degrees C. Preincubation with choleragenoid in vitro does not interfere with this effect of the toxin. Animals pretreated by an intravenous injection of cholera toxin do not respond to the in vitro addition of cholera toxin and NAD to the same extent as untreated animals; i.e., the effects overlap to suggest that the in vitro effect is the same as that in vivo. Responses to isoproterenol, glucagon, and NaF were also similar in the in vitro broken cell-activated system, as previously reported for the enzyme activated in vivo. 相似文献
8.
Guensberg P Wacheck V Lucas T Monia B Pehamberger H Eichler HG Jansen B 《Chemotherapy》2002,48(4):189-195
BACKGROUND: Resistance to chemotherapy in glioblastoma has been linked to the expression of antiapoptotic Bcl-2 family members including Bcl-xL. METHODS: Bcl-xL expression was specifically reduced in M059K glioblastoma cells with antisense oligonucleotides (ISIS 16009, ISIS 16967) as assessed by Western blotting. Induction of apoptosis by treatment with antisense oligonucleotides in combination with paclitaxel in cell culture was monitored by WST-1 assays and flow cytometric analysis. RESULTS: Antisense oligonucleotide-mediated reduction of Bcl-xL levels led to enhanced cytotoxicity in M059K cells when compared to the use of a mismatch control oligonucleotide (p < 0.001). A decreased threshold for the induction of apoptosis led to significantly enhanced cytotoxic responses to paclitaxel treatment in WST-1 assays (p < 0.001) and flow cytometric analyses. CONCLUSION: Combination treatment using Bcl-xL antisense oligonucleotides and paclitaxel may qualify as a promising strategy to ultimately improve the clinical outcome of glioblastoma. 相似文献
9.
Thierry AR Vives E Richard JP Prevot P Martinand-Mari C Robbins I Lebleu B 《Current opinion in molecular therapeutics》2003,5(2):133-138
Antisense oligonucleotides and short interfering RNAs are routinely used for gene function analysis and are being developed for clinical applications. The mechanism underlying internalization of free oligonucleotides into cells is poorly understood and inefficient in most cases. Antisense oligonucleotide delivery into ex vivo cells is routinely improved by the addition of cationic lipids. New chemical modifications and vectors allowing improved cellular delivery in vivo are being developed. 相似文献
10.
Dvorchik BH 《Current opinion in molecular therapeutics》2000,2(3):253-257
Antisense oligonucleotides hold great promise as novel therapeutic agents designed to specifically and selectively inhibit the production of various disease-related gene products. For efficacy to occur, the therapeutic entity must reach the site of action in amounts sufficient to produce the desired therapeutic effect. Pharmacokinetics is defined as the study of the time course of the absorption, distribution, metabolism and elimination (ADME) of drugs. An understanding of the pharmacokinetics of antisense oligonucleotides and, in particular, the mechanisms by which oligonucleotides accumulate in tissues and in cells are critical to understanding the limitations of this technology and ultimately the development of effective antisense therapeutics. This review summarizes the known observations on the pharmacokinetics of antisense oligonucleotides with particular attention to contributions (non-clinical and clinical) published during the interval 1997 to 2000. Principles underlying the ADME of oligonucleotides are presented at the beginning of each section. 相似文献
11.
12.
This article will examine recent developments concerning the cellular uptake and subcellular trafficking of antisense oligonucleotides. It will also examine the merits of various delivery strategies for oligonucleotides. The use of conjugates of oligonucleotides with 'cell penetrating peptides' as a promising delivery technology will be emphasized. 相似文献
13.
Cytosolic delivery of antisense oligonucleotides by listeriolysin O-containing liposomes 总被引:1,自引:0,他引:1
Antisense oligodeoxynucleotides (ODNs) possess great potential as sequence-specific therapeutic agents. Sufficient concentrations of intact ODN must bypass membrane barriers and access the cytosol and nucleus, for ODNs to be therapeutically effective. A cytosolic delivery strategy was designed to improve the efficiency of ODN delivery in bone-marrow-derived macrophages. This liposome-based formulation utilizes listeriolysin O (LLO), the endosomolytic hemolysin from Listeria monocytogenes, to mediate the escape of ODN from endocytic compartments into the cytosol. To monitor the cytosolic delivery of ODN, subcellular trafficking of fluorescently labeled ODNs was visualized using epifluorescence microscopy. The expression of target protein and mRNA after delivery was measured using flow cytometry and Northern blot analysis, respectively. ODN specific for murine intercellular adhesion molecule-1 (ICAM-1) encapsulated in LLO-liposomes was released to the cytosol and trafficked to the nucleus, efficiently and specifically suppressing activation-induced expression of ICAM-1 at both protein and mRNA levels. Delivery without LLO resulted in sequestration of ODN in vesicular compartments leading to little inhibition of ICAM-1 expression, which supports the requirement of LLO for efficient cytosolic delivery using this system. The data clearly demonstrate that LLO-mediated escape of ODN from intracellular vesicles is an effective approach to achieve full therapeutic antisense activity in cultured macrophages. 相似文献
14.
15.
Irene Marafini 《Annals of medicine》2018,50(5):361-370
Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the gastrointestinal tract encompassing two main clinical entities: Crohn’s disease (CD) and ulcerative colitis (UC). These disorders are characterized by various grades of tissue damage and development of local complications and extra-intestinal manifestations. The cause of IBD remains unknown but accumulating evidence indicates that both CD and UC arise in genetically predisposed individuals as a result of the action of multiple environmental factors, which ultimately trigger excessive and poorly controlled immune response against antigens of the luminal flora. Despite this realization, a full understanding of IBD pathogenesis is still out of reach and, consequently, treatment is far from optimal. However, in recent years, several pathways of intestinal damage have been delineated and the improved knowledge has contributed to the development of new therapies. Various approaches have been used to either inhibit the expression and/or function of inflammatory molecules or enhance counter-regulatory mechanisms. This review summarizes the available pre-clinical and clinical data for antisense oligonucleotides and oligonucleotide-based therapy to provide a comprehensive understanding of the rationale and mechanism of action of these compounds in IBD.
- Key messages
Preclinical studies and clinical trials show that antisense oligonucleotide (ASO)-based therapy could be of benefit in inflammatory bowel diseases.
ASOs have an excellent safety profile.
Technical issues emerged from clinical trials suggest that changes in drug formulation and/or route of administration could improve ASO efficacy.
16.
Therapeutic potential of antisense oligonucleotides as modulators of alternative splicing 总被引:12,自引:0,他引:12
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An estimated 60% of all human genes undergo alternative splicing, a highly regulated process that produces splice variants with different functions. Such variants have been linked to a variety of cancers, and genetic diseases such as thalassemia and cystic fibrosis. This Perspective describes a promising approach to RNA repair based on the use of antisense oligonucleotides to modulate alternative splicing and engender the production of therapeutic gene products. 相似文献
17.
目的探讨脂质体介导的p65反义寡核苷酸(ASODN)对大鼠急性出血坏死性胰腺炎(ANP)的作用。方法72只大鼠随机分成假手术组、胰腺炎组、脂质体组、ASODN组(20OD ml)、ASODN+脂质体组、随机ODN组,观察各组大鼠术后6h及12h胰腺病理、血清淀粉酶、血清IL-1、TNF-α、胰腺组织核转录因子(NF-κB)活性的变化。结果同假手术组相比,各处理组的血清淀粉酶活性、IL-1、TNF-α水平、胰腺组织NFκB活性明显升高(P<0.01),但各处理组间的血清淀粉酶活性差异无显著性。同胰腺炎组相比,脂质体组和随机ODN组的胰腺病理评分、血清IL-1、TNF-α、胰腺组织NFκB活性的差异有显著性(P<0.05),而ASODN组和ASODN+脂质体组的胰腺病理评分、血清IL-1、TNF-α、胰腺组织NFκB活性下降(P<0.05),其中ASODN+脂质体组下降更为明显。结论脂质体介导的p65反义寡核苷酸可明显抑制ANP大鼠的血清致炎性细胞因子的表达,改善胰腺病理,提示NF-κB在急性胰腺炎(AP)的发病机制中起关键性调控作用,其p65ASODN可应用于AP的治疗。 相似文献
18.
Effective intracellular delivery of oligonucleotides in order to make sense of antisense. 总被引:5,自引:0,他引:5
For more than two decades, antisense oligonucleotides (ODNs) have been used to modulate gene expression for the purpose of applications in cell biology and for development of novel sophisticated medical therapeutics. Conceptually, the antisense approach represents an elegant strategy, involving the targeting to and association of an ODN sequence with a specific mRNA via base-pairing, resulting in an impairment of functional and/or harmful protein expression in normal and diseased cells/tissue, respectively. Apart from ODN stability, its efficiency very much depends on intracellular delivery and release/access to the target side, issues that are still relatively poorly understood. Since free ODNs enter cells relatively poorly, appropriate carriers, often composed of polymers and cationic lipids, have been developed. Such carriers allow efficient delivery of ODNs into cells in vitro, and the mechanisms of delivery, both in terms of biophysical requirements for the carrier and cell biological features of uptake, are gradually becoming apparent. To become effective, ODNs require delivery into the nucleus, which necessitates release of internalized ODNs from endosomal compartments, an event that seems to depend on the nature of the delivery vehicle and distinct structural shape changes. Interestingly, evidence is accumulating which suggests that by modulating the surface properties of the carrier, the kinetics of such changes can be controlled, thus providing possibilities for programmable release of the carrier contents. Here, consideration will also be given to antisense design and chemistry, and the challenge of extra- and intracellular barriers to be overcome in the delivery process. 相似文献
19.
Romanova EA Levina AA Tsibul'skaia MM Eremenko LL Kaplanskaia IB Shitareva IV Tsyba NN 《Klinicheskaia laboratornaia diagnostika》2000,(4):24, 33-24, 34
Iron metabolites were measured in liver homogenates and leukocytes of patients with hereditary hemochromatosis (HHC), chronic viral hepatitis, and secondary iron overloading. Iron and ferritin levels in the liver are increased HHC, while in hepatitis only ferritin level is increased. In the leukocytes ferritin concentrations are increased both in HHC and secondary iron loading and less so in viral hepatitis. The leukocytic ferritin level decreased after a course of bleeding sessions and during maintenance therapy for HHC, which can serve as a diagnostically significant sign for evaluating the treatment efficiency. 相似文献