Accelerating Wound Healing Using RNAi

描述(申请人提供)：日益增长的老年人口和患有II型糖尿病的人发展成慢性伤口的风险很高，愈合速度很慢。促进伤口愈合的有效疗法可以大大改善那些面临慢性创伤的人以及受伤的军事人员和其他急性创伤的人的生活。Somagenics已经开发了一个基于RNAi的治疗平台，短shRNA(SshRNA)，当它被配方用于有效的肝脏递送时，为该公司的丙型肝炎的主要治疗计划产生了非常有希望的临床前数据。在这里，我们建议开发一种sshRNA治疗策略来促进伤口愈合。该方法涉及下调一种调节多种因素的蛋白质，包括热休克蛋白的合成，众所周知，热休克蛋白通过促进血管生成、血管生成和巨噬细胞募集来加速伤口愈合。另一种靶点的干预有望促进角质形成细胞的生长和运动，这两个过程对伤口闭合至关重要。第一阶段的目标是确定和验证一对化学修饰的寡核苷酸制剂，这些制剂能够有效地抑制这些相应的靶点，并在组织培养模型中产生有利于伤口愈合的下游效应。对于第二阶段，我们计划使用一个成熟的小鼠伤口愈合模型来测试这些抑制剂在不同配方下的体内疗效。 与公共卫生相关：促进伤口快速愈合和愈合并降低感染风险的治疗方法将使军人和平民都受益。在这方面，我们计划开发的基于寡核苷酸的疗法具有优势：它们稳定，不需要冷藏，它们有望在不同的配方中发挥作用，并且它们可以产生长期的治疗效果。这些抑制剂通过针对军队和平民人群的伤口，包括慢性伤口、压疮、静脉溃疡，特别是糖尿病溃疡，应该提供显著的健康影响，对于这些伤口，有巨大的医疗需求和节省医疗费用的潜力。

DESCRIPTION (provided by applicant): The growing populations of the elderly and those with type-II diabetes are at high risk for developing chronic wounds that are slow to heal. Effective therapeutics to promote wound healing can significantly improve the lives of those faced with chronic wounds as well as injured military personnel and others with acute wounds. Somagenics has developed an RNAi-based therapeutic platform, short shRNA (sshRNA), which, when formulated for effective liver delivery, generated very promising preclinical data for the company's lead therapeutic program of hepatitis C. Here we propose the development of an sshRNA therapeutic strategy to accelerating wound healing. The approach involves down-regulating a protein that regulates multiple factors including the synthesis of heat shock proteins, which are known to accelerate wound healing by promoting angiogenesis, vasculogenesis, and macrophage recruitment. Intervention with a separate target is expected to enhance keratinocyte growth and motility, two processes critical for wound closure. The goal of Phase I is to identify and validate a pair of chemically-modified oligonucleotide agents that are effective in inhibiting these respective targets and produce downstream effects beneficial to wound healing in tissue culture models. For Phase II, we plan to use a well-established murine wound-healing model to test the in vivo efficacy of these inhibitors under various formulations. PUBLIC HEALTH RELEVANCE: Therapeutics that promote rapid wound closure and healing and reduce the risk of infection would benefit both military and civilian populations. In this regard, the oligonucleotide-based therapeutics that we are planning to develop have advantages: they are stable and do not require refrigeration, they are expected to be active in different formulations, and they can produce long-lasting therapeutic effects. These inhibitors should provide a significant heath impact by targeting wounds in both military and civilian populations, including chronic wounds, pressure ulcers, venous ulcers, and especially diabetic ulcers, for which there is enormous medical need and potential for savings in healthcare costs