A Novel Anti-inflammatoryand Anti-oxidant Therapy for Treating Non-healing Diabetic Foot Ulcers

SUMMARY Delayed or impaired wound healing is a serious complication of diabetes, often leading to lower limb amputations. By 2050, 1 in 3 Americans will develop diabetes, and up to 34% of diabetic patients will develop a diabetic foot ulcer (DFU) in their lifetime. Current treatments for DFUs include debridement, infection control, maintaining a moist wound environment, and pressure offloading. Despite these interventions, a large number of DFUs fail to heal and are associated with a cost that exceeds $31 billion annually. Chronic inflammation and increased oxidative stress have been implicated in the pathogenesis of the diabetic wound healing impairment. We have designed and tested a new therapeutic that synergistically targets both inflammation and oxidative stress using novel cerium oxide nanoparticles (CNP), which possess reactive oxygen species (ROS) scavenging properties, conjugated with an anti-inflammatory microRNA mimic (miR146a) that is deficient in diabetic wounds and inhibits the activation of NFκB-induced pro-inflammatory response. Importantly, our novel patented conjugate CNP-miR146a efficiently delivers miR146a into the wound to reduce inflammation and ROS, and accelerate wound healing. We have developed a CNP-miR146a specifically formulated for intradermal injection (CTX-001) for the treatment of DFUs. Our preliminary studies demonstrate that a one-time intradermal administration of CTX-001 to full-thickness wounds fully corrects the wound healing impairment in diabetic mice and elicits a significant 25% improvement in wounds in diabetic pigs, essentially by normalization of inflammation and oxidative stress. Repeated weekly administration can correct the diabetic wound healing impairment, similar to healing in non- diabetic wounds. Following a Pre-IND meeting with the FDA and having completed a pilot bulk drug substance cGMP manufacturing of CTX-001, the objective of this Direct to Phase II application by Ceria Therapeutics (Ceria) is to complete cGMP-grade manufacturing and analysis of CTX-001 drug product (Specific Aim 1) to fulfill IND-enabling studies. Specific Aim 2 will confirm the preclinical efficacy of CTX-001 in diabetic (Db/Db) mice and a porcine model of diabetic wound healing; we will assess the role of infection on the efficacy of CTX-001 in mice, and optimize the dose and frequency of administration of CTX-001 to enhance efficacy in the correction of the impaired healing in diabetic pigs. In Specific Aim 3, we will carry out a dose-range finding acute toxicity study of CTX-001 in both rats and minipigs, followed by IND-enabling repeat dose toxicology studies. In vitro genotoxicity studies and an irritation/sensitization study in guinea pigs will complete safety studies in preparation for First-in-Human clinical trials with our lead product.