Targeted heat activation of HSP promoters in the skin of mammalian animals and humans

Abstract

The use of highly inducible HSP promoters for exerting spatial and/or temporal control over the expression of therapeutic transgenes has long been discussed. Localized and time-limited induction of the heat shock response may potentially also be of medical interest. However, such applications would require targeted delivery of heat doses capable of activating HSP promoters in tissues or organs of interest. Accessible areas, including the skin and tissues immediately underneath it, may be most readily targeted. A few applications for heat-directed or heat-controlled therapy in the skin might involve expression of proteins to restore or protect normal skin function, protein antigens for vaccination/immunotherapy, vaccine viruses or even systemically active proteins, e.g., cytokines and chemokines. A review of the literature relating to localized heat activation of HSP promoters and HSP genes in the skin revealed that a multitude of different technologies has been explored in small animal models. In contrast, we uncovered few publications that examine HSP promoter activation in human skin. None of these publications has a therapeutic focus. We present herein two, clinically relevant, developments of heating technologies that effectively activate HSP promoters in targeted regions of human skin. The first development advances a system that is capable of reliably activating HSP promoters in human scalp, in particular in hair follicles. The second development outlines a simple, robust, and inexpensive methodology for locally activating HSP promoters in small, defined skin areas.

Immunization by Replication-Competent Controlled Herpesvirus Vectors

“…A single ulipristal dose can be administered orally at the time of immunization. Regarding heat treatment, we have developed small pads that conduction heat the inoculation region by crystallization of a supercooled salt solution ( 52 ). The pads are capable of maintaining a temperature of 45°C for 15 min.…”

Immunization by replication-competent controlled herpesvirus vectors

“…A single ulipristal dose can be administered orally at the time of immunization. Regarding heat treatment, we have developed small pads that conduction-heat the inoculation region by crystallization of a supercooled salt solution (51). The pads are capable of maintaining a temperature of 45°C for 15 min.…”

Herpes Simplex Viruses Whose Replication Can Be Deliberately Controlled as Candidate Vaccines

“…For example, the promoter of the human HSP70B (HSPA7) gene has a very low basal activity in cultured cells and a heat-induced activity that is almost 1000-fold higher [26,29,30]. In the skin of human subjects, topical heat treatment was found to increase the activity of the latter promoter several hundred times [31]. Significant activation of the promoter in human cells requires heat treatments at temperatures exceeding 42 • C, i.e., at temperatures that only occur in patients experiencing hyperpyrexia.…”

“…For example, disposable/recyclable or reusable heating pads may be employed. A pad that contains a supercooled solution of the essentially nontoxic salt sodium thiosulfate pentahydrate has been tested in human subjects [31]. After crystallization is triggered mechanically, the pad heats up rapidly and maintains a surface temperature of about 45 • C for at least 15 min.…”

“…If this interval were respected, two visits to a physician's office might be required, one for vaccine administration and a second for the heat treatment. However, a second visit with the physician could be avoided by providing inoculated subjects with a simple heating device such as a small pad that is heated by crystallization of a supercooled, nontoxic salt solution (as described in more detail previously [31]) as well as instructions for when and how to self-apply the device. Alternatively, it may be possible to more closely space vaccine administration and heat treatment, making it feasible to complete the entire vaccination procedure during a single visit.…”