Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2009-5-22
pubmed:abstractText
Replicating viruses have broad applications in biomedicine, notably in cancer virotherapy and in the design of attenuated vaccines; however, uncontrolled virus replication in vulnerable tissues can give pathology and often restricts the use of potent strains. Increased knowledge of tissue-selective microRNA expression now affords the possibility of engineering replicating viruses that are attenuated at the RNA level in sites of potential pathology, but retain wild-type replication activity at sites not expressing the relevant microRNA. To assess the usefulness of this approach for the DNA virus adenovirus, we have engineered a hepatocyte-safe wild-type adenovirus 5 (Ad5), which normally mediates significant toxicity and is potentially lethal in mice. To do this, we have included binding sites for hepatocyte-selective microRNA mir-122 within the 3' UTR of the E1A transcription cassette. Imaging versions of these viruses, produced by fusing E1A with luciferase, showed that inclusion of mir-122 binding sites caused up to 80-fold decreased hepatic expression of E1A following intravenous delivery to mice. Animals administered a ten-times lethal dose of wild-type Ad5 (5x10(10) viral particles/mouse) showed substantial hepatic genome replication and extensive liver pathology, while inclusion of 4 microRNA binding sites decreased replication 50-fold and virtually abrogated liver toxicity. This modified wild-type virus retained full activity within cancer cells and provided a potent, liver-safe oncolytic virus. In addition to providing many potent new viruses for cancer virotherapy, microRNA control of virus replication should provide a new strategy for designing safe attenuated vaccines applied across a broad range of viral diseases.
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-11313778, http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-11679670, http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-12007417, http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-12042766, http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-12500980, http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-15215884, http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-16314451, http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-16633348, http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-16690359, http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-17179747, http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-17259931, http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-17368621, http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-18026085, http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-18246077, http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-18710328, http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-18719391, http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-18779050, http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-18799589, http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-211182, http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-8083541, http://linkedlifedata.com/resource/pubmed/commentcorrection/19461878-8892868
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
1553-7374
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
5
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
e1000440
pubmed:dateRevised
2009-11-18
pubmed:meshHeading
pubmed-meshheading:19461878-Adenoviridae, pubmed-meshheading:19461878-Adenovirus E1A Proteins, pubmed-meshheading:19461878-Alanine Transaminase, pubmed-meshheading:19461878-Amino Acid Sequence, pubmed-meshheading:19461878-Animals, pubmed-meshheading:19461878-Artificial Gene Fusion, pubmed-meshheading:19461878-Aspartate Aminotransferases, pubmed-meshheading:19461878-Binding Sites, pubmed-meshheading:19461878-Cell Line, Tumor, pubmed-meshheading:19461878-Fluorescence, pubmed-meshheading:19461878-Gene Expression Regulation, Viral, pubmed-meshheading:19461878-Hepatocytes, pubmed-meshheading:19461878-Humans, pubmed-meshheading:19461878-Liver, pubmed-meshheading:19461878-Liver Neoplasms, Experimental, pubmed-meshheading:19461878-Mice, pubmed-meshheading:19461878-Mice, Inbred BALB C, pubmed-meshheading:19461878-MicroRNAs, pubmed-meshheading:19461878-Molecular Sequence Data, pubmed-meshheading:19461878-Oncolytic Virotherapy, pubmed-meshheading:19461878-Tissue Distribution, pubmed-meshheading:19461878-Whole Body Imaging
pubmed:year
2009
pubmed:articleTitle
Use of tissue-specific microRNA to control pathology of wild-type adenovirus without attenuation of its ability to kill cancer cells.
pubmed:affiliation
Department of Clinical Pharmacology, University of Oxford, Oxford, United Kingdom.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't