Synthetic DNA-compacting peptides derived from human sequence enhance cationic lipid-mediated gene transfer in vitro and in vivo

Cationic lipids can deliver genes efficiently in vitro, but are generally i nhibited by the presence of serum, and their efficiency in vivo is much low er than in vitro. An attractive strategy is to induce strong DNA compaction by its association with proteins, before addition of lipids. However the u se of whole proteins might present both production and immunological limita tions. We have devised a system in which DNA is associated with short pepti des derived from human histone or protamine, before the addition of a catio nic lipid or polymer. Peptides strongly associating with DNA confer to such peptide-DNA-lipid particles an enhanced in vitro transfection efficiency o ver that observed with classical DNA/lipid lipoplexes, and particularly con fer the capacity to transfect in the presence of serum. This acquisition of serum resistance is cell type-independent, and observed with all four lipo polyamines tested and polyethylenimine. Precompacting DNA with a histone H1 -derived peptide enhances cationic lipid RPR 115335-mediated gene transfer in an in vivo model of Lewis lung carcinoma. Apart from their use in peptid e-DNA-lipid association, such peptides could be useful as part of chimeric gene delivery vectors presenting a DNA-binding moiety that can be easily as sociated with other functional domains.