Non-immunostimulatory nonviral vectors.
The vectors for gene delivery are usually classified as viral and nonviral vectors. While the viral vectors are very efficient in transducing cells, safety concerns regarding their use in humans make nonviral vectors an attractive alternative. Among the nonviral vectors, the lipoplexes (complexes of cationic liposome/pDNA) are the most studied and represent the most promising approaches for human clinical trials. However, an inflammatory response is invariably associated with administration of the lipoplexes, which must be avoided in the clinical application. Here, we have successfully developed a nonimmunostimulatory vector for gene therapy. The vector possesses dual functions of: 1) efficiently delivering a gene to target cells and 2) codelivering DNA and inflammatory suppressors into the immune cells where the released suppressor can inhibit cytokine production. The inflammatory suppressors successfully delivered by the vector included glucocorticoids, a nonsteroidal anti-inflammatory drug (NSAID), an NF-kappaB inhibitor, and a natural compound from an herbal medicine. Intravenous injection of the vector dramatically suppressed the cytokine production induced by CpG motif pDNA, including TNF-alpha, IL-12 and IFN-gamma. This new gene vector has a great potential in clinical gene therapy. Another potential use of the vector is codelivery of an enhancer candidate, acting at the transcriptional and translational levels to improve the efficiency of gene transfer by the nonviral vector. Moreover, the unique feature of this vector is that it can be used as an easy and powerful tool for in vivo screening of anti-inflammatory drugs.
Liu
Feng
F
The center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA. fliu@pitt.edu or leafh@pitt.edu
Shollenberger
Lisa M
LM
Huang
Leaf
L
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002412:Cations; D016207:Cytokines / Q000096:biosynthesis*; D005822:Genetic Vectors / Q000737:chemistry* / Q000633:toxicity*; D007249:Inflammation / Q000139:chemically induced; D008081:Liposomes; D051379:Mice; D010957:Plasmids / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000893:Anti-Inflammatory Agents; D002412:Cations; D016207:Cytokines; D008081:Liposomes; D014409:Tumor Necrosis Factor-alpha