Although RNA interference offers therapeutic potential for treating skin disorders, delivery hurdles have hampered clinical translation. We have recently demonstrated that high pressure, resulting from
intradermal injection of large liquid volumes, facilitated
nucleic acid uptake by keratinocytes in mouse skin. Furthermore, similar
intradermal injections of
small interfering RNA (
siRNA; TD101) into
pachyonychia congenita (PC) patient foot lesions resulted in improvement. Unfortunately, the intense
pain associated with
hypodermic needle administration to PC lesions precludes this as a viable delivery option for this disorder. To investigate
siRNA uptake by keratinocytes, an organotypic epidermal model, in which pre-existing endogenous gene or reporter gene expression can be readily monitored, was used to evaluate the effectiveness of "self-delivery"
siRNA (i.e.,
siRNA chemically modified to enhance cellular uptake). In this model system, self-delivery
siRNA treatment resulted in reduction of pre-existing fluorescent reporter gene expression under conditions in which unmodified controls had little or no effect. Additionally, treatment of PC epidermal equivalents with self-delivery "TD101"
siRNA resulted in marked reduction of mutant
keratin 6a mRNA with little or no effect on wild-type expression. These results indicate that chemical modification of
siRNA may overcome certain limitations to transdermal delivery (specifically keratinocyte uptake) and may have clinical utility for inhibition of gene expression in the skin.