Development of non-viral vectors for systemic gene delivery

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Abstract

One of the major challenges for gene therapy is systemic delivery of a nucleic acid directly into an affected tissue. This requires developing a vehicle which is able to protect the nucleic acid from degradation, while delivering the gene of interest to the specific tissue and specific subcellular compartment. In this review, we summarize some of the recent advances in new non-viral delivery systems for systemic administration. Two types of gene delivery systems are described: (i) LPD1 (cationic liposome-entrapped, polycation-condensed DNA, type 1), and (ii) retention-time mediated naked DNA delivery. Hypothesized mechanisms for these systemic gene transfers are also discussed.

Introduction

Research in gene therapy has demonstrated potential for treatment of both acquired and inherited diseases. This approach is based on the principle of correcting the basis of a diseases at their origin by delivery and subsequent expression of exogenous DNA, which encodes for a missing or defective gene product. Therefore, gene therapy will make it possible to circumvent some limitations of protein drugs, including low bioavailability, high cost of manufacturing, and repeated parenteral administration due to the poor pharmacokinetic parameters, such that DNA may become a drug of choice.

Vehicles for gene delivery, which have successfully demonstrated the delivery of exogenous genes in vivo, can be divided into two major groups: viral and non-viral vectors. Viral vectors include retrovirus, adenovirus, adeno-associated virus, herpes simplex virus and lentivirus. In general, viruses are very efficient gene-transfer vehicles; however, significant limitations are inherent to their use. Viral vectors may provoke mutagenesis and carcinogenesis. Repeated administration of a viral vector induces an immune response which abolishes the transgene expression. Considering these limitations, non-viral vectors such as cationic liposomes, polymers, naked DNA, etc. offer an attractive alternative. Non-viral vectors are being developed under the assumption that they will overcome problems associated with viral gene delivery. However, non-viral delivery vehicles are still relatively inefficient.

This review will focus on systemic gene delivery using new non-viral systems recently developed in our laboratory, including LPD1 (cationic liposome-entrapped, polycation-condensed DNA, type 1) and retention-time mediated naked DNA delivery. The proposed mechanism of gene transfer through systemic administration will also be discussed in this review. The extracellular environment remains the major obstacle to systemic administration, and characterization of the in vivo barriers will help in efforts to design more efficient non-viral vectors which will achieve therapeutic effect. Understanding of mechanisms of the fundamental biophysical interactions will permit further optimization of non-viral vector systems for systemic gene delivery.

Section snippets

Development of LPD1

A primary demonstration of in vivo transgene expression was performed through the use of a pH-sensitive liposomal vector, which encapsulated DNA and was conjugated with an antibody ligand to transfect mouse ascitic tumors [1]. Low entrapment efficiency and high serum sensitivity of the pH-sensitive liposomes prevented its application on a broader scale until the introduction of the first cationic lipid, DOTMA (2,3-dioleyloxypropyl-1-trimethylammonium bromide) [2]. Thereafter, many additional

Sequential injection of cationic liposomes and naked plasmid DNA

To minimize in vivo blood-washing force for plasmid DNA, and to increase the retention time of naked DNA in the lung, a sequential injection strategy has been developed, in which free cationic liposomes were injected first into mice followed by naked plasmid DNA 5 min later [27]. The injected cationic liposomes will form aggregates in the blood, which are likely to be trapped in the lung capillaries. Therefore, subsequently injected plasmid DNA, otherwise easily flowing through the lung

Conclusion

Several routes of gene delivery using non-viral vectors have been examined, including intravenous injection, intratracheal instillation, and intratissue injection, among which systemic gene delivery is the most challenging. When a vector is administered intravenously, the clearance by the reticuloendothelial system (RES), and the presence of large amounts of serum nucleases, lipases, opsonins, etc., greatly diminishes the chances of the vector reaching the target tissue. However, with more

Acknowledgements

The work is partially supported by NIH grants AR 45925, DK 54225, DK 44935, CA 74918, AI 48851 and by a grant from the Muscular Dystrophy Association of America. We thank Dr Mark McCord Whitmore for allowing us to use Fig. 1.

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