(692c) Localized Sustained Delivery of siRNA for the Treatment of Diabetic Ulcers

Castleberry, S., Oklahoma State University

Wound healing is a complex and highly synchronized process of multiple biological pathways, consisting of an assortment of signaling molecules including many growth factors, which evolves over time with the progression of the wound.  Development of drug delivery system that can locally modify cell behavior on the basic level of gene transcription provides a powerful tool to alter the pathology of wound healing.  RNA interference is a highly specific gene silencing process mediated through the use of short interfering RNAs (siRNA) that has the potential to be an extremely powerful therapeutic tool in medicine. 

Impaired wound healing is a major problem in diabetes, leading to the development of more than 750,000 diabetic foot ulcers and 70,000 lower extremity amputations per year in the USA alone.  Recent work in understanding the molecular mechanisms underlying poor wound resolution in diabetic patients have shown increased expression of metalloproteinase 9 (MMP-9) correlates with poor outcomes.  Small interfering RNA (siRNA) has emerged as a powerful tool in post-transcriptional gene silencing.  In this work we describe the development and implementation of a polymer-based thin film that successfully delivered siRNA for the knockdown of MMP-9 expression within the wounds of genetically diabetic mice.  This reduction resulted in significantly accelerated wound healing and increased collagen deposition within the wound bed. 

Developing the capability to effectively deliver siRNA locally and in a way that addresses the complications common in diabetic wound healing would significantly advance the current state of diabetic ulcer treatment.  This work presents an opportunity to substantially improve the treatment of patients and outcomes.