Recent Advances in Non‐viral Gene Delivery

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Abstract

Gene therapy has been deemed the medicine of the future due to its potential to treat many types of diseases. However, many obstacles remain before gene delivery is optimized to specific target cells. Over the last several decades, many approaches to gene delivery have been closely examined. By understanding the factors that determine the efficiency of gene uptake and expression as well as those that influence the toxicity of the vector, we are better able to develop new vector systems. This chapter will provide a brief overview of recent advances in gene delivery, specifically on the development of novel non‐viral vectors. The following chapters will provide additional details regarding the evolution of non‐viral gene delivery systems.

Introduction

Gene delivery holds great promise as a therapeutic agent for a vast array of medical ailments including cancer, genetic disorders and acquired diseases. The ideal gene delivery vehicle would exhibit cell specificity, minimal immune response, efficient release of DNA into cells, and have a large DNA capacity. Viral vectors such as attenuated viruses, adenoviruses and retroviruses, have thus far proven to have significantly more efficient gene expression than most non‐viral vectors. The success of viral vectors has been severely limited due to the potential for a specific immune response to the vector that could hinder gene delivery as well as elicit a severe inflammatory reaction and cause nonspecific gene integration into the host genome. Non‐viral vectors are not expected to elicit a specific immune response or randomly integrate DNA into the genomic DNA of the host and therefore are looked to as the future of gene delivery systems. Non‐viral vectors include cationic polymer and lipid‐based encapsulation of DNA as well as the delivery of naked DNA by physical mechanisms. Although non‐viral vectors are considered superior vehicles for gene delivery due to their decreased immunogenicity, their success has been severely limited by inefficient cellular uptake and gene expression. Recent advances made in the field of non‐viral gene delivery, specifically strategies to improve target specificity and gene uptake and release, and to further reduce the nonspecific immune response, are addressed briefly below.

Section snippets

Cationic Lipids

Felgner et al. reported the use of lipid‐based vectors in the late 1980s and since then these vesicles have been considered one of the most promising methods for non‐viral gene delivery (Felgner et al., 1987). The cationic head groups make strong electrostatic associations with the DNA, eventually leading to the collapse of the anionic polymer. The length and degree of saturation of the lipid chain is significant in determining the stability and toxicity of the liposome. To form a stable

Cationic Polymers

Cationic polymers condense DNA into compact structures by neutralizing the anionic charge on the DNA. The resulting cationic polymer/DNA complexes, or polyplexes, encapsulate the DNA into small particles for gene delivery. Common polycations include polylysine, polyamines such as polyethylenimine, histone proteins, polyarginine‐containing proteins (i.e., protamine, HIV‐TAT), and cationic dendrimers. As with lipids, not all cationic polymers are optimal for gene delivery and issues such as

Triggered Release

A recurring issue with both lipid and cationic polymer‐based non‐viral vectors is the release of DNA once the particle is taken into the cell. Many vectors are able to efficiently bind to the target cells; however, the gene expression was lower than expected. A primary example of this is the cationic lipid containing the folate ligand. Particles were small (i.e., less than 50 nm) and association with target cells was observed, yet gene expression was not efficient (Dauty 2002, Zuber 2003). Some

Physical Delivery Methods for Naked DNA

Delivery of naked DNA to cells elicits minimal immune response as compared to DNA encapsulated in lipids or cationic polymers. The lack of immunogenicity of naked DNA makes it a good prospect for gene therapy. The limitations with this approach arise in that naked DNA is unprotected against nuclease degradation and the DNA does not have target specificity. Thus, the actual physical delivery of naked DNA must be directed towards the tissues of interest since no target ligands are attached to the

Prospects

Many recent advances in non‐viral gene therapy have significantly increased the prospect for these methods as successful gene delivery agents. The improved proficiency of cell targeting has increased the potential for cell‐specific gene delivery as well as increased uptake as the vectors are attracted to receptors on the cell surface. Additionally, the triggered release technology should enhance the DNA release into the cells, further increasing the gene expression. The increased uptake and

Acknowledgment

The original work from this lab has been supported by NIH grants CA74918, AI48851, DK44935, DK68556, and AR45925.

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