To the editor:

Gene therapy is based on the delivery of therapeutic genes into target cells. Strategies for gene transfer has been limited so far to two approaches using either viral vector or non viral vector methods, but recent data published in Nature Biotechnology suggest a new approach based on bacteria-mediated gene delivery1. Traditional strategies are based on the assumption that the introduction of a therapeutic gene into target cells is a prerequisite step to any successful gene therapy. The concept of gene therapy can be reformulated however, if we consider the delivery of the therapeutic gene at the cell surface as an alternative to its penetration into cells. Such targeting at the cell surface could be achieved by the use of mycoplasma2.

Mycoplasmas are the smallest self-replicating living organisms, with a genome in some cases less than 600 kilobases. They are extracellular parasites intimately associated with the surface of the cells they parasitize3. Thus, the delivery and the expression of a therapeutic gene at the cell surface, rather than inside, via mycoplasmas could present an alternative to the current concepts and vectors used in gene therapy to produce secreted drugs or proteins.

An interesting feature of mycoplasmas is that they can behave as commensal organisms. Thus, they usually cause only mild symptoms with a tendency to latent infection4. This protection against host defense is probably related to the close contact of mycoplasmas to host cell membrane, their ability to adsorb host antigens at their surface, and their antiphagocytic surface properties4.

In addition, many of the endotoxic substances and antigens found on the cell wall of Gram negative bacteria are absent in mycoplasmas, which are naturally wall-less organisms. Another potential advantage of this approach would be the reduced risk of recombination between DNA constructs and the genome of host cells, since therapeutic DNA remains at the cell surface. Therefore, mycoplasma-mediated gene therapy could well represent an attractive alternative for the production of either cell-permeant drugs or secreted proteins such as a growth factors or hormones.