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

Mol Ther. 2013 Jan;21(1):101-8. doi: 10.1038/mt.2012.161. Epub 2012 Aug 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cytosine Deaminase / genetics*
  • Genetic Engineering*
  • Humans
  • Injections, Intralesional
  • Mice
  • Neurilemmoma / genetics
  • Neurilemmoma / pathology*
  • Pentosyltransferases / genetics
  • Polymerase Chain Reaction
  • RNA, Messenger / genetics*

Substances

  • RNA, Messenger
  • Pentosyltransferases
  • uracil phosphoribosyltransferase
  • Cytosine Deaminase