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

在美国，每年有大约60万个临床治疗的烧伤创面。经济复苏 这些烧伤创面需要长时间的愈合，在此之前可能需要长达一年或更长的时间 有完全的组织再生。在许多情况下，烧伤患者会留下难看的疤痕。 改善创面愈合的早期阶段一直是创面愈合治疗的一个主要焦点。 伤口愈合有三个不同的阶段：最初的炎症阶段(阶段1)； 增殖期(第二阶段)；和长期组织重塑阶段(第三阶段)，恢复 皮肤恢复到伤口前的状态。大多数创新继续只推广第一阶段，要么是通过 新材料(合成和生物)，可以更好地清洁和保护受伤组织，或者通过 调节免疫反应。这些方法对于诱使伤口进入很重要。 第二阶段，但对加速较长的组织再生和增殖过程几乎没有作用 正在改建%1。因此，为了改善患者预后，需要一种安全有效的治疗方法。 这加快了伤口愈合的早期阶段(阶段1和阶段2)，并导致更多的 有效闭合和有效成熟的伤口(阶段3)。 Fidgetin-like 2(Fl2)是一种新近发现的微管细胞骨架调节因子。 并解聚微管。下调Fl2表达增强的微管 在体外促进细胞运动和促进临床和组织学愈合的功能 小鼠动物模型2。MicroCures的目标是开发一种局部纳米siRNA疗法 针对这种新型靶点(Fl2-NP-si；SiFI2)直接促进创面闭合和真皮 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，促进组织修复。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，降低感染风险，缩短 住院时间，减少疤痕形成。 在第一阶段，烧伤创面再上皮化增强17%，创面缩小30%； 伤口处胶原沉积和成熟显著改善；并增加 在猪烧伤模型中观察到了再神经支配和血管形成。 SiF2。这项第二阶段的提案将启动IND申请的步骤，包括制定 生产GMP SiF2所需的化学、制造和控制。这将是 完成三个具体目标：(1)启动GMP启动计划；(2)评估潜力 体外毒性问题；以及(3)直接比较CMO生产的SiFi2与用于 活体疗效研究的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.