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Keratinocytes are a very attractive vehicle for ex wVo gene transfer and systemic delivery, since proteins secreted by these cells may reach the circulation via a mechanism which mimics the natural process. A n efficient retroviral vector (LXSN) encoding the mouse growth hormone gene (mGH) was used to transduce primary human keratinocytes. Organotypic raft cultures were prepared with these genetically modified keratinocytes and were grafted onto immunodeficient dwarf mice {lit/scid). Transduced keratinocytes presented a high and stable in vitro secretion level of up to 11 |ag mGH/10^cells/day. Conventional epidermal sheets made with these genetically modif ied keratinocytes, however, showed a drop in secretion rates of > 8 0 % simply due to detachment of the epithelium from its substratum. Substitution of conventional grafting methodologies with organotypic raft cultures completely overcame this problem. The stable long-term grafting of such cultures onto immunodeficient dwarf {lit/scid) mice could be fol lowed for more than 4 months, and a significant weight increase (P<0.05) over the control group was observed in the first 40 days. Circulating mGH levels revealed a peak of 21 ng/mL just 1h after grafting, but unfortunately these levels rapidly fell to baseline values ( 2 ng/mL). mGH-secret ing primary human keratinocytes presented the highest in vitro expression and peak circulatory levels reported to date for a form of GH with this type of cells. Together with data showing that excised implants can recover in culture a remarkable fraction of their original in vitro mGH secretion efficiency, the factors that might still hamper the success of this promising model of cutaneous gene therapy are discussed.

Secreção de hormônio de crescimento de camundongo por queratinócitos humanos primários: perspectivas para um modelo animal de terapia gênica cutânea