Summary

Synthetic vectors have been applied to a wide range of inherited and acquired diseases, and this review has covered only

Figure 4 Synthetic gene delivery to promote wound healing. Cationic lipid-pDNA complexes can be injected subcutaneously at sites near the wound margin. Alternatively, pDNA can be embedded in a collagen or fibrin matrix. Cells migrating into the matrix take up the pDNA and express a given soluble factor.

Figure 4 Synthetic gene delivery to promote wound healing. Cationic lipid-pDNA complexes can be injected subcutaneously at sites near the wound margin. Alternatively, pDNA can be embedded in a collagen or fibrin matrix. Cells migrating into the matrix take up the pDNA and express a given soluble factor.

a small list of disorders for which synthetic vectors have been used. Efficacy has been demonstrated in several animal models and clinical trials have been conducted. The preclinical and clinical results revealed genuine promise but also definite limitations that should perhaps serve as a cautionary sign for moving synthetic vectors too aggressively into clinical use.

Safety is of prime concern for any gene therapy, and although synthetic vectors are generally safe, an acute inflammatory response is observed with certain vector systems and delivery routes. Naked DNA delivery into muscle appears to present the least number of complications, with a minimal (but not totally benign) inflammatory response and little to no systemic toxicity. In contrast, cationic lipid or polycatio-nic-pDNA complexes induce a dose-dependent toxic response when delivered by aerosol into the lung or injected systemically. The response observed in CF patients that received aerosolized complex was transient and treatable symp-tomatically with analgesics. However, systemically delivered complex induces a much more severe reaction, especially at higher doses, and no clinical use with this delivery route can be foreseen until this toxicity is resolved. Less toxic vectors and formulations, which include CpG-depleted vectors and smaller nonaggregating complexes, are under development. But for now, any proposed clinical application should consider the possible consequences of the innate immune reaction to current synthetic vector systems.

Gene transfer efficiency continues to be the paramount limitation of current synthetic vectors. The many published preclinical results demonstrating some degree of efficacy are generally using delivery methods or doses that would not be clinically acceptable, and most studies have been in small animals such as mice, where the levels of expression observed are often not translatable to larger animals and humans. Therefore, generating therapeutic levels of a protein to replace that which is absent in a given inherited genetic disease is probably unrealistic with the current technology. More feasible is expressing modulating proteins, such as cytokines to inhibit inflammation, tumor-specific antigens to induce an immune response, or growth factors to promote angiogenesis or cell proliferation. These approaches, as well as related strategies in which synthetic gene transfer serves as an adjunct therapy to existing therapies, may be more appropriate and have greater chances of clinical success.

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