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

在美国，每年约有600，000例临床治疗的烧伤伤口。恢复 从这些烧伤伤口涉及长期愈合，可能需要长达一年或更长的时间， 组织完全再生在许多情况下，烧伤的受害者留下了毁容的疤痕。 改善伤口愈合的早期阶段一直是伤口愈合治疗的主要焦点。 伤口愈合发生在三个不同的阶段：初始炎症阶段（阶段1）; 增殖期（2期）;以及恢复组织再生的长组织重建期（3期）。 皮肤恢复到受伤前的状态大多数创新只继续推动第一阶段， 新材料（合成和生物），更好地清洁和保护受伤的组织，或通过 调节免疫反应。这些方法对于引导伤口进入 阶段2，但几乎没有加速组织再生的较长增殖过程， 改造1.因此，为了改善患者的预后，需要一种安全有效的治疗方法。 加速伤口愈合的早期阶段（阶段1和2）， 有效闭合和有效成熟的伤口（第3阶段）。 Fidgetin-like 2（FL 2）是最近发现的微管细胞骨架调节因子， 并解聚微管。FL 2表达的下调增强了微管 在体外促进细胞运动，并在临床和组织学上改善愈合， 鼠动物模型2. MicroCures旨在开发局部纳米颗粒siRNA治疗 该新靶点（FL 2-NP-si; SiFi 2）直接增强伤口闭合和真皮 成纤维细胞和角质形成细胞的成熟功能，从而提供了 加速伤口愈合和改善组织修复。因此，伤口愈合可以发生更多 快速，高保真，从而减少忍受的疼痛，降低感染的风险，缩短 住院时间和减少疤痕 在第一阶段，17%的烧伤创面再上皮化增强，30%的创面大小缩小; 显著改善伤口部位的胶原蛋白沉积和成熟; 在猪烧伤模型中观察到神经再支配和血管化， SiFi 2。该第二阶段提案将启动IND申请的步骤，包括制定 生产GMP SiFi 2所需的化学、生产和控制。这将是 完成了三个具体目标：（1）启动GMP启动计划;（2）评估潜在的 体外毒性问题;以及（3）直接比较CMO产生的SiF 12与用于制备SiF 12的材料。 体内疗效研究的I期。

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.