The epidermis as a bioreactor: topically regulated cutaneous delivery into the circulation.
Previous studies have documented that the skin can be used as a bioreactor to produce proteins for systemic release to treat diseases. A gene-switch system has been developed that allows regulated expression of therapeutic genes. To determine whether this system could be used in the skin, we developed a transgenic mouse model in which expression of a therapeutic gene could be topically induced in epidermal keratinocytes. After a single induction, high levels of the therapeutic protein, human growth hormone (hGH), were released from keratinocytes into the circulation. The serum levels of hGH were dependent on the amount of inducer applied, and repeated induction resulted in increased weight gain by transgenic versus control mice. Furthermore, physiological levels of hGH were detected in the serum of nude mice after topical induction of small transgenic skin grafts. These results clearly demonstrate the feasibility of using the gene-switch system to regulate the delivery of therapeutic proteins into the circulation via genetically modified keratinocytes.
Cao
Tongyu
T
Pacific Biomedical Research Center, University of Hawaii at Manoa, Honolulu, HI 96822, USA.
Tsai
Sophia Y
SY
O'Malley
Bert W
BW
Wang
Xiao-Jing
XJ
Roop
Dennis R
DR
D000818:Animals; D019149:Bioreactors; D001835:Body Weight; D004817:Epidermis / Q000378:metabolism*; D005240:Feasibility Studies; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D019382:Human Growth Hormone / Q000097:blood / Q000235:genetics*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D015735:Mifepristone / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011980:Receptors, Progesterone / Q000235:genetics
D011980:Receptors, Progesterone; D019382:Human Growth Hormone; D015735:Mifepristone