Genetically engineered microvesicles carrying suicide mRNA/protein inhibit schwannoma tumor growth.
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.
Department of Neurology and Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA.
Arda
A
Mizrak
Mehmet Fatih
MF
Bolukbasi
Gokhan Baris
GB
Ozdener
Gary J
GJ
Brenner
Sibylle
S
Madlener
Erdogan Pekcan
EP
Erkan
Thomas
T
Ströbel
Xandra O
XO
Breakefield
Okay
O
Saydam
D000818:Animals; D002460:Cell Line; D043525:Cytosine Deaminase / Q000235:genetics*; D005818:Genetic Engineering; D006801:Humans; D015552:Injections, Intralesional; D051379:Mice; D009442:Neurilemmoma / Q000235:genetics / Q000473:pathology*; D010430:Pentosyltransferases / Q000235:genetics; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics*
D012333:RNA, Messenger; D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; D043525:Cytosine Deaminase