Articles: oligonucleotides.
-
Clusterin is a cytoprotective chaperone protein that promotes cell survival and confers broad-spectrum treatment resistance. OGX-011 is a 2'-methoxyethyl-modified phosphorothioate antisense oligonucleotide that is complementary to clusterin mRNA, has a prolonged tissue half life, enhances drug efficacy in xenograft models, and reduces clusterin expression in humans with a biologically effective dose of 640 mg. The objective of this study was to determine a recommended phase II dose of OGX-011 in combination with docetaxel. ⋯ OGX-011 can be given at a biologically effective dose with standard doses of docetaxel. Phase II trials of combined OGX-011 and chemotherapy are ongoing in patients with prostate, breast, and lung cancers.
-
Duchenne's muscular dystrophy is associated with severe, progressive muscle weakness and typically leads to death between the ages of 20 and 35 years. By inducing specific exon skipping during messenger RNA (mRNA) splicing, antisense compounds were recently shown to correct the open reading frame of the DMD gene and thus to restore dystrophin expression in vitro and in animal models in vivo. We explored the safety, adverse-event profile, and local dystrophin-restoring effect of a single, intramuscular dose of an antisense oligonucleotide, PRO051, in patients with this disease. ⋯ Intramuscular injection of antisense oligonucleotide PRO051 induced dystrophin synthesis in four patients with Duchenne's muscular dystrophy who had suitable mutations, suggesting that further studies might be feasible.
-
To present an overview of antisense technology and to review and assess available literature on the chemistry, pharmacology, pharmacokinetics, drug interactions, preclinical and clinical studies, dosing, and adverse events of ISIS 301012 in the treatment of hyperlipidemia. ⋯ ISIS 301012 is the first agent to enter clinical trials utilizing an antisense mechanism for reducing the production of apolipoprotein B. Further studies are needed to verify its safety, efficacy, and position of therapy in the dyslipidemic patient.
-
Int. J. Radiat. Oncol. Biol. Phys. · Jul 2007
Antisense-MDM2 sensitizes LNCaP prostate cancer cells to androgen deprivation, radiation, and the combination in vivo.
To test the effects of antisense (AS)-MDM2 alone and with androgen deprivation (AD), radiotherapy (RT), and AD + RT on wild-type LNCaP cells in an orthotopic in vivo model. ⋯ This is the first in vivo investigation of the effects of AS-MDM2 in an orthotopic model and the first to demonstrate incremental sensitization when added to AD and AD + RT. The results with AD underscore the potential to affect micrometastatic disease, which is probably responsible for treatment failure in 30-40% of men with high-risk disease.
-
Expert Opin Biol Ther · Jun 2007
ReviewPotential of oligonucleotide-mediated exon-skipping therapy for Duchenne muscular dystrophy.
Many of the mutations associated with Duchenne muscular dystrophy can potentially be rescued by exon-skipping therapy, targeting selected exons of prespliced mRNA for the dystrophin gene with antisense oligonucleotides, thereby restoring reading frames. The recent development of antisense oligonucleotides with higher stability and lower toxicity, such as morpholinos, has made it possible to restore dystrophin efficiently in dystrophic mice in vivo with no obvious side effects. There seems little doubt that such exon-skipping therapy is destined to proceed to the clinical application stage in patients with Duchenne muscular dystrophy. ⋯ At present, this multi-exon skipping strategy is being investigated in dystrophic dogs as well as dystrophic mice. There are several challenges that still need to be overcome, including the low uptake of antisense oligonucleotides into the heart and the need to design efficient, nontoxic, cost-effective oligonucleotides. This review summarizes recent progress in exon-skipping therapy and discusses future perspectives with regard to human clinical trials.