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PMID: 22910294 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Genetically engineered microvesicles carrying suicide mRNA/protein inhibit schwannoma tumor growth.

Molecular therapy : the journal of the American Society of Gene Therapy ·Vol. 21 ·No. 1 ·2013-01-00 ·Pages 101-8

Mizrak A, Bolukbasi MF, Ozdener GB, Brenner GJ, Madlener S, Erkan EP, Ströbel T, Breakefield XO, Saydam O

Abstract

Microvesicles (MVs) play an important role in intercellular communication by carrying mRNAs, microRNAs (miRNAs), non-coding RNAs, proteins, and DNA from cell to cell. To our knowledge, this is the first report of delivery of a therapeutic mRNA/protein via MVs for treatment of cancer. We first generated genetically engineered MVs by expressing high levels of the suicide gene mRNA and protein-cytosine deaminase (CD) fused to uracil phosphoribosyltransferase (UPRT) in MV donor cells. MVs were isolated from these cells and used to treat pre-established nerve sheath tumors (schwannomas) in an orthotopic mouse model. We demonstrated that MV-mediated delivery of CD-UPRT mRNA/protein by direct injection into schwannomas led to regression of these tumors upon systemic treatment with the prodrug (5-fluorocytosine (5-FC)), which is converted within tumor cells to 5-fluorouracil (5-FU)-an anticancer agent. Taken together, these studies suggest that MVs can serve as novel cell-derived "liposomes" to effectively deliver therapeutic mRNA/proteins to treatment of diseases.

MeSH Terms
Animals Cell Line Cytosine Deaminase/genetics Genetic Engineering Humans Injections, Intralesional Mice Neurilemmoma/genetics,pathology Pentosyltransferases/genetics Polymerase Chain Reaction RNA, Messenger/genetics
Chemicals
RNA, Messenger Pentosyltransferases uracil phosphoribosyltransferase Cytosine Deaminase
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Mizrak Arda
Department of Neurology and Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA.
Bolukbasi Mehmet Fatih
Ozdener Gokhan Baris
Brenner Gary J
Madlener Sibylle
Erkan Erdogan Pekcan
Ströbel Thomas
Breakefield Xandra O
Saydam Okay
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Article Info
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
Abbr.
Mol Ther
ISSN
1525-0024
DOI
10.1038/mt.2012.161
Published
2013-01-00
Epub
2012-00-21
Pages
101-8
Language
English
Region
United States
NLM ID
100890581
PMCID
PMC3538300
Subset
IM
Grants
NCI NIH HHS · CA141150 · United States
NCI NIH HHS · R01 CA141150 · United States
NCRR NIH HHS · S10 RR025504 · United States
NINDS NIH HHS · P01 NS037409 · United States
NINDS NIH HHS · NS037409 · United States
External Links
PubMed source DOI: 10.1038/mt.2012.161 PMC Full Text View journal details
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