An immunomodulatory approach to improve oral cavity wound healing

About This Grant

PROJECT SUMMARY Wound healing complications following injury to the oral tissues from surgery or trauma can lead to significant pain and need for revision surgeries. Cleft palate occurs in 1:1000 live births all undergo palate surgery; how- ever, 60% develop complications including oronasal fistula (ONF) formation which often recur. ONF also occur after traumatic oral injury or dental surgery representing a critical unmet need in clinical care. The physical con- sequences of ONF formation lead to pain, poor feeding and poor speech. Currently, there are no regenerative options to mitigate the complications of oral injury or surgery leading to significant pain and cost due to need for multiple revision ONF surgeries. Our group has developed a novel murine phenocopy of ONF, and identi- fied that FTY720, an active biolipid, targets the sphingosine pathway to preferentially attract proregenerative immune cells to improve ONF healing and reduce pain. Our long-term goal is to optimize FTY720 delivery as an immunoregenerative therapy to improve oral wound healing and reduce pain. The overall objective in this application is to determine the mechanism of FTY720-guided ONF healing and optimize FTY720 delivery. The central hypothesis is that FTY720 reduces the inflammatory neutrophils, monocytes and macrophages during oral cavity wound healing through genetic, epigenetic, and sphingolipid pathways and that the chemical struc- ture of FTY720 can be optimized to attract pro-regenerative immune cells leading to improved wound healing and reduced pain. The rationale for the proposed research is that a comprehensive and mechanistic under- standing of FTY720’s immunoregenerative function during ONF healing will provide mechanistic insights into oral wound healing and allow the optimization of FTY720 as the first oral regenerative therapy. Guided by strong preliminary data from the parent grant, including a paper demonstrating the immune cell changes during FTY720-guided ONF healing, the hypothesis will be tested by pursuing two specific aims: 1) Investigate FTY720-based therapeutic mechanisms during ONF healing via integrated spatiotemporal metabolic and tran- scriptomic profiling; 2) Optimize FTY720’s delivery using novel formulations to enhance its immunomodulatory and analgesic properties in vitro and in vivo. In Aim 1 we will define the genetic, epigenetic and sphingolipid signaling mechanisms through which FTY720 is altering the immune system and regenerating the oral tissues. In Aim 2, we will engineer the delivery of FTY720 to optimize bioavailability and therapeutic efficacy to improve ONF healing and reduce pain. The proposed research is innovative by mechanistically characterizing FTY720’s ability to heal ONF as a model for all oral wound healing and optimization of FTY720 towards the first immunoregenerative therapy for oral wound healing. The proposed research is significant because FTY720, an FDA-approved drug approved to treat multiple sclerosis, could be fast tracked to clinical trials to allow ONF healing, improve pain and reduce opioid dependence.