Abstract
Appropriate gene delivery systems are essential for successful gene therapy in clinical medicine. Lipid-mediated nucleic acid delivery is an alternative to viral vector-mediated gene delivery and has the following advantages. Lipid-mediated delivery of DNA or mRNA is usually more rapid than viral-mediated delivery, offers a larger payload, and has a nearly zero risk of incorporation. Lipid-mediated delivery of DNA or RNA is therefore preferable to viral DNA delivery in those clinical applications that do not require long-term expression for chronic conditions. Delivery of RNA may be preferable to non-viral DNA delivery in some clinical applications, since transit across the nuclear membrane is not necessary, and onset of expression with RNA is therefore even faster than with DNA, although both are faster than most viral vectors. Delivery of RNA to target organ(s) has previously been challenging due to RNA’s rapid degradation in biological systems, but cationic lipids complexed with RNA, as well as lipid nanoparticles (LNPs), have allowed for delivery and expression of the complexed RNA both in vitro and in vivo. This review will focus on the non-viral lipid-mediated delivery of RNAs, including mRNA, siRNA, shRNA, and microRNA, to the central nervous system (CNS), an organ with at least two unique challenges. The CNS contains a large number of slowly dividing or non-dividing cell types and is protected by the blood brain barrier (BBB). In non-dividing cells, RNA-lipid complexes demonstrated increased transfection efficiency relative to DNA transfection. The efficiency, timing of the onset, and duration of expression after transfection may determine which nucleic acid is best for which proposed therapy. Expression can be seen as soon as 1 h after RNA delivery, but duration of expression has been limited to 5–7 h. In contrast, transfection with a DNA lipoplex demonstrates protein expression within 5 h and lasts as long as several weeks after transfection.
Highlights
Gene therapy has the potential to significantly advance clinical medicine, but the risks and duration of gene delivery should be closely matched to the proposed clinical application [1]
We present here a review of the progress made in delivery of nucleic acids, RNAs, to the central nervous system (CNS)
Transfection by delivery to the cisterna magna of rats of a cationic lipid:pDNA-fLUC complex provides widespread CNS expression of luciferase, which peaks at approximately 72 h but is visible by real time bioluminescence imaging using the In Vivo Imaging System (IVIS) by Caliper
Summary
Gene therapy has the potential to significantly advance clinical medicine, but the risks and duration of gene delivery should be closely matched to the proposed clinical application [1]. For clinical applications in which only short-term gene expression is required or warranted, the delivery of nucleic acids (DNA or RNA, including mRNA, siRNA, shRNA, and microRNAs saRNA) by means of non-viral vectors, chemical-based carriers, such as cationic lipids, cationic polymers, or lipid nanoparticles, provide a far more favorable risk/benefit ratio. The structure and size of these complexes affect transfection efficacy and vary with temperature, concentration, charge ratio, buffer, time, and lipid composition These lipid/nucleic acid complexes protect the nucleic acids from degradation in the extracellular environment [7,8]. Barriers to lipid or polymer-mediated nucleic acid transfection include: (1) transport of the nucleic acid/lipid complex through the extracellular environment to target tissue(s);.
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