Controlled release of RNA-targeting therapy to promote healing of diabetic ulcers

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Project Summary Non-healing ulcers are a common complication of diabetes, resulting in decreased quality of life, elevated rates of amputation, increased risk of mortality, and high healthcare costs. Unfortunately, current treatments remain outdated and inadequate. In diabetes, neuropathy and microvascular changes in dermal tissue lead to dysregulated molecular cues, resulting in chronic inflammation and reduced angiogenesis that prevent wound healing. Poor angiogenesis is particularly critical given the importance of vasculature in supplying oxygen, nutrients, and systemic signaling molecules. Impairment of angiogenesis is in part driven by aberrant expression of coding messenger RNAs (mRNAs) and non-coding microRNAs (miRNAs) at various time scales. Thus, one promising approach to alter the course of diabetic ulcers is to directly target the expression of upregulated RNAs in the non-healing state using nucleic acid RNA-targeting therapies; however, delivery challenges render nucleic acid therapies clinically unfeasible. To address these delivery challenges, the Hammond Lab has developed and demonstrated self-assembled electrostatic deposition of nucleic acids through the layer by layer (LbL) technique, which leverages iterative adsorption of polyelectrolytes of alternating charge, to create conformal coatings on wound bandages with tunable release kinetics. I propose to develop and investigate temporally controlled release strategies to locally deliver RNA-targeting therapies that promote angiogenesis and healing of diabetic ulcers. In Aim 1, I will formulate staged release RNA-targeting bandages to promote wound healing since staged release of therapy for multiple targets will allow the bandages to address different phases of wound healing. A proof-of-concept bandage will be developed to elute RNA-targeting therapy to stimulate angiogenesis in both the inflammatory and proliferative wound healing phases, and it will be tested for efficacy in vitro and in a murine in vivo diabetic ulcer model. In Aim 2, I will identify potential synergies of pro-angiogenic anti-miRs (miRNA inhibitors), as inhibition of gene expression with anti-miRs enables regulation of many genes along defined tissue-specific signaling pathways to enhance angiogenesis. Since it is also unknown how delivery timing of these anti-miR combinations may impact efficacy, we will leverage controlled-release LbL bandages to investigate this. Through this research, I will advance the delivery of nucleic acids with biomaterial systems and the targeting of aberrantly expressed coding and non-coding RNAs to promote healing of diabetic wounds. This work will lay the groundwork for expansion of this platform approach to other diseases of impaired tissue regeneration where timing the delivery to the healing process is critical, such as venous ulcers, mesenteric ischemia, and myocardial infarction.