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. 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. As strategies for wound care have evolved from skin grafts and passive dressings to biopharmaceutical approaches, most innovation has continued to promote only Phase 1, either with new materials that better clean and protect the wounded tissue, or with growth factors and/or other factors that modulate the immune response. These approaches are important for coaxing a wound to enter Phase 2, but do little to for remodeling and repair of the tissue (Phase 3). Additionally, excessive use of growth-factor-containing products has been found to increase lifetime cancer risk in patients1. 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 (FL2-NP-si), to directly enhance the wound-closure and dermal maturation function of fibroblasts and keratinocytes thereby addressing, for the first time, the challenge of accelerated healing and tissue repair in acute wounds. 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. The goal for this proposed project is to characterize a standard formulation of FL2-NP-si in terms of efficacy and safety in two animal models, Yorkshire pig (Specific Aim 1) and Sprague-Dawley rat (Specific Aim 2), in preparation for IND-enabling studies. Time to wound healing and histopathology at the wound site will be evaluated in both animal models. In addition, whole- animal histopathology and the maximum tolerated dose will be determined in Specific Aim 2. At the end of the project period, we will show that FL2-NP-si is both safe and efficacious for the treatment of burn wounds, and is ready for IND-enabling studies.