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BackgroundOligonucleotides belong to a class of macromolecules with great potential for research and various therapeutic applications. Their mechanisms of action are extremely diverse, although they are rather homogeneous in composition. Single-stranded oligodeoxynucleotides are not only inhibitors of gene expression, but their CpG sequence motifs may activate the innate immune response. Recent progress made in preclinical and clinical testing, as well as the case of the most recently discovered RNA interference technology, will help to overcome efficacy problems of the previous approaches of the ‘standard therapy’ of such diseases as tumors and various infections.MethodsThe aim of this article is to present various therapeutic aspects of oligonucleotides, and to review the most significant therapeutic applications of synthetic oligonucleotides. This paper presents a comprehensive review of current literature on various therapeutic properties of synthetic oligonucleotides.ConclusionsThe available results gathered from preclinical and clinical studies suggest that TLR9-targeted therapy of oligonucleotides can stimulate both innate and adaptive immunity. It also appears that CpG ODNs are generally safe, although moderate adverse effects, based on a backbone-related mechanism have been reported. The presented studies demonstrate that adjuvant CpG ODN can unify an immune response that leads to enhanced antigen-specific Ab formation. CpG ODN may therefore provide a unique approach to enhancing the efficacy of immunization, including the strengthening of antitumor immunity. 相似文献
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Laura Rabinovich-Guilatt Anna Elgart Lavi Erisson Sandra K Willsie Shoshi Tessler Ofra Barnett-Griness Amitkumar Pande Ofer Spiegelstein 《British journal of clinical pharmacology》2015,80(3):436-445
Aims
Custirsen (OGX-011/TV-1011), a second-generation antisense oligonucleotide (ASO) that reduces clusterin production, is under investigation with chemotherapy in patients with solid tumours. Custirsen is associated with constitutional symptoms (CS) that may interfere with clinical pharmacology investigations, such as QT interval studies. Experience with other ASOs suggests NSAID premedication may ameliorate CS, but we observed suboptimal outcomes in healthy subjects given custirsen and NSAIDs. We sought to establish a custirsen regimen for future clinical pharmacology studies in healthy subjects.Methods
Subjects received custirsen (640 mg intravenously over 120 min) with dexamethasone premedication or increasing doses (320, 480, 640 mg over 6 days) of custirsen with dexamethasone premedication, then one full custirsen dose without premedication on day 8. Incidence/severity of adverse events (AEs) and extensive electrocardiogram readings were evaluated. Pharmacokinetic parameters were estimated.Results
AEs included CS, elevated transaminases and prolonged activated partial thromboplastin time (aPTT) that were predominantly grade 1/2. Administration of increasing custirsen doses and dexamethasone premedication reduced the incidence of CS associated with full dose custirsen. Transaminase elevation showed a dose-dependent effect (0% at days 2, 4, 27% at day 6) with the highest custirsen doses. Increasing doses of custirsen may have mitigated the severity but not incidence of aPTT prolongation. Neither regimen was associated with cardiac repolarization changes in QT values or concentration–effect analyses. The custirsen pharmacokinetic profile was consistent with previous experience.Conclusion
Escalation of custirsen dose combined with dexamethasone premedication reduced CS associated with full dose custirsen and should be considered in future clinical pharmacology studies of custirsen. 相似文献39.
目的探讨敲低miR-21表达对人胶质瘤细胞系U87细胞功能的影响以及相关作用机制。方法脂质体介导转染miR-21反义寡聚核苷酸(miR-21 inhibitor)敲低U87细胞miR-21的表达。使用实时荧光定量PCR鉴定转染后U87细胞miR-21表达水平;MTT法检测转染后细胞增殖水平,流式法评价转染后细胞周期分布及凋亡变化,并结合Western印迹及RT-PCR验证在U87细胞中miR-21和hTERT间关系。结果体外转染反义miR-21寡聚核苷酸能明显抑制U87细胞生长,诱导其凋亡,并且能够明显下调hTERT表达。结论反义miR-21可能通过下调hTERT表达抑制胶质细胞生长,miR-21可作为胶质瘤基因治疗的靶点。 相似文献
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Sample R Bryan L Long S Majji S Hoskins G Sinning A Olivier J Chinchar VG 《Virology》2007,358(2):311-320
Frog virus 3 (FV3) is a large DNA virus that encodes approximately 100 proteins. Although the general features of FV3 replication are known, the specific roles that most viral proteins play in the virus life cycle have not yet been elucidated. To address the question of viral gene function, antisense morpholino oligonucleotides (asMOs) were used to transiently knock-down expression of specific viral genes and thus infer their role in virus replication. We designed asMOs directed against the major capsid protein (MCP), an 18 kDa immediate-early protein (18K) that was thought to be a viral regulatory protein, and the viral homologue of the largest subunit of RNA polymerase II (vPol-IIalpha). All three asMOs successfully inhibited translation of the targeted protein, and two of the three asMOs resulted in marked phenotypic changes. Knock-down of the MCP resulted in a marked reduction in viral titer without a corresponding drop in the synthesis of other late viral proteins. Transmission electron microscopy (TEM) showed that in cells treated with the anti-MCP MO assembly sites were devoid of viral particles and contained numerous aberrant structures. In contrast, inhibition of 18K synthesis did not block virion formation, suggesting that the 18K protein was not essential for replication of FV3 in fathead minnow (FHM) cells. Finally, consistent with the view that late viral gene expression is catalyzed by a virus-encoded or virus-modified Pol-II-like protein, knock-down of vPol-IIalpha triggered a global decline in late gene expression and virus yields without affecting the synthesis of early viral genes. Collectively, these results demonstrate the utility of using asMOs to elucidate the function of FV3 proteins. 相似文献