Linked Life Data

17363479

Source:http://linkedlifedata.com/resource/pubmed/id/17363479

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2007-3-16
pubmed:abstractText
RNA interference has become widely used as an experimental tool to study gene function. In addition, small interfering RNA (siRNA) may have great potential for the treatment of diseases. Recently, it was shown that siRNA can be used to mediate gene silencing in mouse models. Locally administered siRNAs entered the first clinical trials, but strategies for successful systemic delivery of siRNA are still under development. Challenges still exist about the stability, delivery, and therapeutic efficacy of siRNA. In the present study, we compare the efficacy of two methods of systemic siRNA delivery and the effects of siRNA modifications using locked nucleic acids (LNA) in a xenograft cancer model. Low volume tail vein bolus injections and continuous s.c. delivery using osmotic minipumps yielded similar uptake levels of unmodified siRNA by tumor xenografts. Both routes of administration mediated sequence-specific inhibition of two unrelated targets inside tumor xenografts. Previous studies have shown that LNA can be incorporated into the sense strand of siRNA while the efficacy is retained. Modification of siRNA targeting green fluorescent protein with LNA results in a significant increase in serum stability and thus may be beneficial for clinical applications. We show that minimal 3' end LNA modifications of siRNA are effective in stabilization of siRNA. Multiple LNA modifications in the accompanying strand further increase the stability but negate the efficacy in vitro and in vivo. In vivo, LNA-modified siRNA reduced off-target gene regulation compared with nonmodified siRNA. End-modified siRNA targeting green fluorescent protein provides a good trade-off between stability and efficacy in vivo using the two methods of systemic delivery in the nude mouse model. Therefore, LNA-modified siRNA should be preferred over unmodified siRNA.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1535-7163
pubmed:author
pubmed:issnType
Print
pubmed:volume
6
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
833-43
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:17363479-Animals, pubmed-meshheading:17363479-Gene Expression Profiling, pubmed-meshheading:17363479-Gene Silencing, pubmed-meshheading:17363479-Gene Targeting, pubmed-meshheading:17363479-Green Fluorescent Proteins, pubmed-meshheading:17363479-Humans, pubmed-meshheading:17363479-Mice, pubmed-meshheading:17363479-Mice, Inbred Strains, pubmed-meshheading:17363479-Mice, Nude, pubmed-meshheading:17363479-Oligonucleotides, pubmed-meshheading:17363479-Oligonucleotides, Antisense, pubmed-meshheading:17363479-Pancreatic Neoplasms, pubmed-meshheading:17363479-RNA, Small Interfering, pubmed-meshheading:17363479-RNA Stability, pubmed-meshheading:17363479-Tissue Distribution, pubmed-meshheading:17363479-Tumor Cells, Cultured, pubmed-meshheading:17363479-Whole Body Imaging, pubmed-meshheading:17363479-Xenograft Model Antitumor Assays
pubmed:year
2007
pubmed:articleTitle
Evaluation of locked nucleic acid-modified small interfering RNA in vitro and in vivo.
pubmed:affiliation
Department of Neurogenetics, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. o.r.mook@amc.uva.nl
pubmed:publicationType
Journal Article, In Vitro