Systemic Replacement Therapy from Genetically Modified Epidermal Keratinocytes

Abstract

Epidermal keratinocytes are a potential vehicle for gene transfer and systemic delivery. We review data showing that epidermis-secreted protein does indeed reach the circulation, and we discuss factors that bear upon the issue of how much protein epidermal keratinocytes can deliver to the circulation.

Increases in weight of growth hormone‐deficient and immunodeficient (lit/scid) dwarf mice after grafting of hGH‐ secreting, primary human keratinocytes

“…Primary human keratinocytes can be serially propagated in vitro, following the pioneering work of Rheinwald and Green (6), and, compared with other cells, have many unique characteristics that support their utilization as vehicles for the delivery of gene products by means of grafting (7,8). Transduced, hGH-secreting keratinocytes apparently provide an attractive method for systemic delivery of the hormone in view of reports that epidermis-secreted protein can reach the circulation (8,9) and especially since clinical autologous grafting techniques and surgical protocols have already been optimized (10)(11)(12). A number of researchers have followed this approach using retrovirus-mediated transduction, or classical DNA transfection, of primary keratinocytes in conjunction with the athymic mouse as an animal model.…”

Tissue-engineered skin substitutes in regenerative medicine

“…Control of expression of the transfected gene In applications to genetic disease, the choice of gene to transfect is dictated by the disease addressed, such as genes for the components of laminin-332 for treatment of junctional epidermolysis bullosa [15,16,19,20]. In the case of hormone augmentation, Taichman has demonstrated that physiologically useful amounts of growth hormone can be made and reach the blood stream from genetically modified keratinocytes [21] and Tian et al have used a skin substitute to supply insulin in the experimentally diabetic rat [17]. This approach delivers a baseline amount of insulin but is incapable of the rapid and precise release characteristic of the pancreas.…”

Virus-Mediated Gene Transfer for Cutaneous Gene Therapy

“…Khavari and E. Dellambra et al, this issue, pp. 2277-2287and 2283-2287) and replacement therapy for inherited metabolic disorders through cutaneous release of a secreted protein (Petersen et al, 1995;Taichman, 1999) (see T. Cao et al, this issue, pp.…”