Accelerating Wound Healing Using RNAi

利用 RNAi 加速伤口愈合

基本信息

批准号：
8395056
负责人：
Brian H. Johnston
金额：
$ 34.74万
依托单位：
SOMAGENICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-24 至 2014-09-23
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8395056
关键词：
Acute Biological Cell Survival Chronic Complex Cultured Cells Data Decubitus ulcer Development Diabetic ulcer Drug Formulations Elderly General Population Goals Growth Healed Health Care Costs Heat shock proteins Hepatitis C Human Hypoxia Immune Infection Intervention Lead Lipids Liver Mediating Medical MicroRNAs Military Personnel Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Oligonucleotides Pathway interactions Pharmaceutical Preparations Phase Population Process Protein Secretion Proteins RNA RNA Interference Refrigeration Resistance Risk Savings Skin Stem cells Surgical Flaps Testing Therapeutic Therapeutic Effect Tissues Varicose Ulcer Vascular Endothelial Growth Factors Work Wound Healing angiogenesis base cell motility design diabetic healing high risk improved in vivo inhibitor/antagonist injured keratinocyte macrophage migration mouse model nanoparticle novel therapeutic intervention nuclease open wound pre-clinical programs small hairpin RNA tissue culture transcription factor uptake vasculogenesis wound

项目摘要

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

描述（由申请人提供）：老年人和II型糖尿病的人群不断增长，患有慢性伤口的愈合缓慢的风险很高。有效促进伤口愈合的有效治疗方法可以显着改善患有慢性伤口的人的生活，受伤的军事人员和其他急性伤口的生活。体体已经开发了一个基于RNAi的治疗平台Short ShRNA（SSHRNA），该平台为有效的肝脏递送而制定，为公司的肝炎铅治疗程序生成了非常有前途的临床前数据。我们在这里提出，我们建议开发SSHRNA治疗策略，以加速伤口愈合。该方法涉及下调一种调节多种因素的蛋白质，包括合成热休克蛋白，已知通过促进血管生成，血管生成和巨噬细胞募集来加速伤口愈合。与单独靶标的干预有望增强角质形成细胞的生长和运动性，这两个过程对于伤口闭合至关重要。第一阶段的目的是识别和验证一对有效抑制这些相应靶标并产生有益于组织培养模型伤口愈合的下游作用的化学改性寡核苷酸剂。对于第二阶段，我们计划使用良好的鼠伤口治疗模型来测试这些抑制剂在各种配方下的体内功效。公共卫生相关性：促进快速伤口封闭和康复并降低感染风险的治疗剂将使军事和平民受益。在这方面，我们计划开发的基于寡核苷酸的治疗剂具有优势：它们是稳定的，不需要制冷，预计它们会在不同的配方中活跃，并且可以产生持久的治疗作用。这些抑制剂应通过针对军事和平民人口的伤口（包括慢性伤口，压力溃疡，静脉溃疡，尤其是糖尿病性溃疡）来产生重大的卫生影响，为此，医疗需求和减少医疗保健费用的潜力