Accelerating Wound Healing Using RNAi

描述（由申请人提供）：老年人和II型糖尿病患者人数不断增加，慢性伤口愈合缓慢的风险很高。促进伤口愈合的有效疗法可以显着改善那些面临慢性伤口以及受伤的军事人员和其他急性伤口的人的生活。Somagenics开发了一种基于RNAi的治疗平台，即短shRNA（sshRNA），当其被配制用于有效的肝脏递送时，为该公司的丙型肝炎领先治疗计划产生了非常有前途的临床前数据。在这里，我们提出了一种sshRNA治疗策略的发展，以加速伤口愈合。该方法涉及下调调节多种因子的蛋白质，包括热休克蛋白的合成，已知热休克蛋白通过促进血管生成、血管发生和巨噬细胞募集来加速伤口愈合。用单独的靶点进行干预有望增强角质形成细胞的生长和运动性，这是伤口闭合的两个关键过程。第一阶段的目标是鉴定和验证一对化学修饰的寡核苷酸试剂，其有效抑制这些相应的靶标，并在组织培养模型中产生有益于伤口愈合的下游效应。对于II期，我们计划使用完善的小鼠伤口愈合模型来测试这些抑制剂在各种制剂下的体内功效。 公共卫生相关性：促进伤口快速闭合和愈合并减少感染风险的治疗方法将使军事和平民受益。在这方面，我们正在计划开发的基于阿托伐他汀的治疗药物具有优势：它们稳定且不需要冷藏，预计它们在不同的制剂中具有活性，并且它们可以产生持久的治疗效果。这些抑制剂应通过靶向军事和平民群体的伤口提供显著的健康影响，包括慢性伤口、压力性溃疡、静脉性溃疡，特别是糖尿病性溃疡，对于这些伤口，存在巨大的医疗需求和节省医疗保健费用的潜力

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