LONG-TERM EXPRESSION OF THE HUMAN ALPHA-1-ANTITRYPSIN GENE IN MICE EMPLOYING ANIONIC AND CATIONIC LIPOSOME VECTOR

The complete process of gene therapy involves three important steps: t argeting, delivery, and gene expression. Since each step can be relate d to the pharmacological concept of affinity, bioavailability, and int rinsic capacity, this commentary examines, from this perspective, the efficiency of anionic and cationic liposomes as vectors for the in viv o gene transfer of the human alpha 1-antitrypsin gene. Small liposomes represent the first generation of liposomes destined for the liver pa renchymal cell. Although the final efficiency of gene transfer is low, we found that small liposomes are a kind of high affinity hepatocyte- destined vector because the dose range for mediating the response is t hree orders of magnitude lower than that used by other procedures. Enc apsulated DNA is more efficient than the cationic liposome-DNA complex for in vivo gene transfer. This could be due to gene bioavailability, since encapsulated DNA is protected from enzymatic digestion, whereas DNA externally associated with the liposome can be digested before th e complex reaches the target cell. However, when the gene transfer eff iciencies of anionic and cationic small liposomes were compared, we ob served a similar rate of efficiency and potency, since equivalent plas ma levels of human protein were observed after the same i.v. dose of r ecombinant plasmid encapsulated in anionic or cationic liposomes. On t he other hand, the elements selected for constructing the expression c assette greatly influence gene expression and the stability of the gen e product, and, therefore, the final efficacy is also limited by the i ntrinsic capacity of a specific expression cassette to express the gen e product. (C) 1997 Elsevier Science Inc.