The Emerging Role of DNA Vaccines

W. Michael McDonnell, MD, Western Washington Medical Group, and Frederick K. Askari, MD, PhD, University of Michigan.

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DNA Delivery Methods -- What is Naked DNA?

Fundamental to any gene therapy strategy is identifying the best vehicle (vector) or packaging system which will enable the gene to get inside the desired cell type and have the desired effect. Current techniques of gene transfer in mammals include packaging the DNA into recombinant viral vectors such as a retrovirus, vaccinia virus or adenovirus; attaching the DNA to cationically charged molecules such as liposomes, calcium salts or dendrimers; or delivering naked DNA to cells. Genes may also be transferred into cells ex vivo, by removing the target tissue (ie, liver cells or white blood cells) from the patient, transferring the gene in vitro and then replanting the transduced cells into the patient.

In 1990, Jon Wolff and associates[7] made a startling discovery. They found that the DNA of a gene inserted into a plasmid alone (naked), when injected intramuscularly in mice, could be taken up by cells and expressed in minute amounts. There was no need for complex vectors. A plasmid is a small circular piece of DNA which can reproduce itself in bacteria and other cells. Plasmids are a common tool in molecular biology for cloning genes, rearranging genes and producing large quantities of DNA or protein in the laboratory.

This method of DNA transfer has its limitations. The number of cells that take up and express the DNA is limited and the amount of gene product expressed is small. Therefore, this method would not be ideal for the treatment of cystic fibrosis because sufficient quantities of the cystic fibrosis transmembrane conductance regulator protein (CFTR) would not be produced in enough cells to have a clinical effect.

However, the amount of gene product made with this approach does appear to be enough to stimulate T cells. The simplicity of this system has made it possible for any lab to place the genes of an antigenic component of any pathogen into a plasmid and begin experiments to test if they have created an effective vaccine. In addition, naked DNA vaccines bypass the problem of safety and manufacturing issues arising when viral vectors are used, as well as complications or interference from an immune response directed at the delivery vector.

Investigators at Agracetus Inc, (Middleton, Wisc.) have added an additional twist to DNA vaccines by delivering the plasmid vaccine on fine gold beads which are implanted into the skin with an air gun.[8] These investigators believe the cells of Langerhans are taking up the DNA for antigen presentation, and they have been able to show efficacy using very small doses of DNA vaccine.

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