Development of A Topical siRNA Therapy to Promote Burn Wound Healing via Depletion of the Novel Microtubule Regulatory, Fidgetin-Like-2

There are ~ 600,000 clinically treated burn wounds in the United States each year. The recovery from these burn wounds involves prolonged healing that can take up to a year or more before there is complete tissue regeneration. In many cases, the burn victim is left with disfiguring scars. Improving early stages of wound healing has been a major focus for wound healing therapeutics. Wound healing occurs in three distinct stages: an initial inflammatory phase (Phase 1); a proliferative phase (Phase 2); and a long tissue remodeling phase (Phase 3) that restores the skin to the pre-wound state. Most innovation has continued to promote only Phase 1, either with new materials (synthetic and biological) that better clean and protect the wounded tissue, or by modulating the immune response. These approaches are important for coaxing a wound to enter Phase 2, but do little to accelerate the longer proliferative processes of tissue regeneration and remodeling1. Thus, to improve patient outcomes there is a need for a safe and effective therapy that expedites both early stages of wound healing (Phases 1 and 2) and results in a more efficiently closed and effectively matured wound (Phase 3). Fidgetin-like 2 (FL2) is a recently discovered regulator of the microtubule cytoskeleton that severs and depolymerizes microtubules. Down-regulation of FL2 expression enhanced microtubule function to promote cell motility in vitro and improved healing both clinically and histologically in murine animal models2. MicroCures aims to develop a topical nanoparticle siRNA treatment to this novel target (FL2-NP-si; SiFi2) to directly enhance the wound-closure and dermal maturation function of fibroblasts and keratinocytes thereby offering the potential to accelerate wound healing AND improve tissue repair. Thus, wound healing can occur more rapidly, with high fidelity, resulting in reduction in endured pain, lower risk of infection, shorter hospital stays, and decreased scarring. During Phase I, 17% enhancement in burn wound re-epithelialization; 30% wound size reduction; significant improvements in collagen deposition and maturation at the wound site; and increased re-innervation and vascularization were observed in a pig burn model following treatment with SiFi2. This Phase II proposal will initiate steps towards an IND filing, including developing the chemistry, manufacturing, and controls necessary for producing GMP SiFi2. This will be accomplished over three specific aims: (1) initiate a GMP start-up program; (2) evaluate potential toxicity issues in vitro; and (3) directly compare the CMO-produced SiFi2 with material used in Phase I in an in vivo efficacy study.