Delivery of MDR1 small interfering RNA by self-complementary recombinant adeno-associated virus vector.
Small interfering RNAs (siRNAs) are potentially powerful tools for therapeutic gene regulation. DNA cassettes encoding RNA polymerase III promoter-driven hairpin siRNAs allow long-term expression of siRNA in targeted cells. A variety of viral vectors have been used to deliver such cassettes to cells. Here we report on the development and use of a self-complementary recombinant adeno-associated virus (scAAV) vector for siRNA delivery into mammalian cells. We demonstrate that this modified vector efficiently delivers siRNA into multidrug-resistant human breast and oral cancer cells and suppresses MDR1 gene expression. This results in rapid, profound, and durable reduction in the expression of the P-glycoprotein multidrug transporter and a substantial reversion of the drug-resistant phenotype. This research suggests that scAAV-based vectors can be very effective agents for efficient delivery of therapeutic siRNA.
Xu
Dong
D
Department of Pharmacology, University of North Carolina, 1017 Mary Ellen Jones, CB# 7365, Chapel Hill, NC 27599-7365, USA.
McCarty
Doug
D
Fernandes
Alda
A
Fisher
Michael
M
Samulski
R J
RJ
Juliano
R L
RL
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D000229:Dependovirus / Q000235:genetics*; D015536:Down-Regulation; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression / Q000187:drug effects; D005822:Genetic Vectors; D006801:Humans; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D009690:Nucleic Acid Conformation; D034622:RNA Interference; D012333:RNA, Messenger / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D004317:Doxorubicin