Integrating DNA vectors for gene therapy

The many platform and poster presentations at the last annual meeting of the American Society for Gene Therapy (ASGT) make it clear that nonviral, integrating DNAs have reached a tipping point in establishing themselves as potential vectors for gene therapy.1 These vectors currently include the Sleeping Beauty (SB) transposon system,2 the first such vector used in gene therapy experiments,3 the ϕC31 and ϕBT1 integrase systems from Streptomyces,4,5 and more recently the insect piggyBac6 and fish Tol27 transposon systems. Several other transposon systems are under development. The common motivations to develop nonviral vectors are their lack of major immunogenic responses, the ease of purification and quality control, and the ability to insert precise sequences into chromosomes (Figure 1). The primary considerations used to evaluate these nonviral vectors have been their 1) activity to insert specific genetic sequences into chromosomes, 2) genetic cargo capacity, 3) sensitivity to different levels of the relevant recombinase, 4) integration-site preferences, and 5) their propensity to induce chromosomal rearrangements. The first three issues pertain to the particular nonviral systems with respect to the capability and ease of achieving a desirable therapeutic end, whereas the latter two concern safety issues