Improving Wound Healing with Topical Gene Therapy

Abstract

Background: Impaired wound healing remains a major clinical problem with many etiologies. Altering gene expression to enhance healing is an innovative therapeutic approach. In recent years, we have developed a means to topically silence genes at the post-transcriptional level to locally alter wounds and improve the healing process.

The problem: Many types of chronic wounds have been associated with alterations in the expression of genes that mediate healing. Targeting the expression of these genes in a way that can improve healing while limiting systemic side effects has been very challenging.

Basic/clinical science advances: Our laboratory's recent work has focused on the use of topically applied small interfering ribonucleic acid (siRNA) to inhibit messenger RNA expression of certain mediators involved in healing in two different types of cutaneous injury-radiation-induced cutaneous injury and the diabetic excisional wound. By successfully inhibiting specific gene mediators with topical siRNA, we reversed downstream signaling pathways, which led to expedited wound healing in diabetic wounds and restoration to a more normal phenotype in radiation-induced skin injuries.

Clinical care relevance: The signaling pathways and gene mediators that we targeted and inhibited in murine models are present in humans. Applying parallel treatment strategies in humans may provide novel means of treating these burdensome and costly conditions.

Conclusion: Our novel method for local gene silencing is effective in treating various types of cutaneous murine wounds. Topical gene silencing with siRNA obviates the side effects of systemic medication and has the potential to be effective in healing or preventing a wide array of cutaneous human conditions.

Pierre B. Saadeh

FIG. 1.

A schematic of topical small interfering ribonucleic acid (siRNA) application on intact skin. A complex of siRNA with agarose is applied over a designated treatment area of skin. siRNA penetrates through the epidermis and has intracellular effects in the epidermis and dermis. Color images available online at www.liebertpub.com/wound

FIG. 2.

Immunohistochemical staining for p53. Reduced expression of p53 (brown staining) is demonstrated within the p53-silenced wound beds compared with control wound beds at postwounding day 10. Color images available online at www.liebertpub.com/wound