Controlled release of RNA-targeting therapy to promote healing of diabetic ulcers

RNA靶向疗法的受控释放促进糖尿病溃疡愈合

• 批准号: 10677024
• 负责人: Adam G Berger
• 金额: $ 5.27万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677024
• 关键词: Address; Adsorption; Amputation; Angiogenesis Inhibitors; Angiogenic Proteins; Antibiotics; Bandage; Biocompatible Materials; Biological; Biological Assay; Blood Vessels; Charge; Chronic; Clinical; Code; Complications of Diabetes Mellitus; Cues; Deposition; Dermal; Diabetes Mellitus; Disease; Dose; Drug Delivery Systems; Effectiveness; Electrostatics; Endosomes; Endothelial Cells; Engineering; Excipients; Gene Expression; Genes; Health Care Costs; Histology; Human; Impaired healing; Impaired wound healing; Impairment; In Vitro; Inflammation; Inflammatory; Investigation; Ischemia; Kinetics; Knowledge; Lead; Macrophage Activation; Malignant Neoplasms; Measures; Mediating; Medicare; Mesentery; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Analysis; Molecular Weight; Mus; Myocardial Infarction; Natural regeneration; Neuropathy; Nucleic Acids; Nutrient; Oxygen; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Polymers; Process; Procollagen-Proline Dioxygenase; Quality of life; RNA; RNA-targeting therapy; Recurrence; Regulation; Research; Signal Pathway; Signaling Molecule; Small Interfering RNA; System; TNF gene; Techniques; Therapeutic; Time; Tissues; Transfection; Translating; Treatment Efficacy; Ulcer; Untranslated RNA; Varicose Ulcer; Vascular Endothelial Growth Factors; Work; Wound models; angiogenesis; chronic ulcer; chronic wound; controlled release; cytokine; decubitus ulcer; diabetic ulcer; diabetic wound healing; effective therapy; efficacy testing; gene function; healing; immune activation; improved; in vitro Assay; in vivo; inhibitor; insight; lipid nanoparticle; mortality; mortality risk; non-healing wounds; nuclease; nucleic acid delivery; nucleic acid-based therapeutics; overexpression; perfusion imaging; prevent; response; self assembly; synergism; targeted treatment; tissue regeneration; tool; uptake; wound; wound care; wound closure; wound environment; wound healing

Project Summary Non-healing ulcers are a common complication of diabetes, resulting in decreased quality of life, elevated rates of amputation, increased risk of mortality, and high healthcare costs. Unfortunately, current treatments remain outdated and inadequate. In diabetes, neuropathy and microvascular changes in dermal tissue lead to dysregulated molecular cues, resulting in chronic inflammation and reduced angiogenesis that prevent wound healing. Poor angiogenesis is particularly critical given the importance of vasculature in supplying oxygen, nutrients, and systemic signaling molecules. Impairment of angiogenesis is in part driven by aberrant expression of coding messenger RNAs (mRNAs) and non-coding microRNAs (miRNAs) at various time scales. Thus, one promising approach to alter the course of diabetic ulcers is to directly target the expression of upregulated RNAs in the non-healing state using nucleic acid RNA-targeting therapies; however, delivery challenges render nucleic acid therapies clinically unfeasible. To address these delivery challenges, the Hammond Lab has developed and demonstrated self-assembled electrostatic deposition of nucleic acids through the layer by layer (LbL) technique, which leverages iterative adsorption of polyelectrolytes of alternating charge, to create conformal coatings on wound bandages with tunable release kinetics. I propose to develop and investigate temporally controlled release strategies to locally deliver RNA-targeting therapies that promote angiogenesis and healing of diabetic ulcers. In Aim 1, I will formulate staged release RNA-targeting bandages to promote wound healing since staged release of therapy for multiple targets will allow the bandages to address different phases of wound healing. A proof-of-concept bandage will be developed to elute RNA-targeting therapy to stimulate angiogenesis in both the inflammatory and proliferative wound healing phases, and it will be tested for efficacy in vitro and in a murine in vivo diabetic ulcer model. In Aim 2, I will identify potential synergies of pro-angiogenic anti-miRs (miRNA inhibitors), as inhibition of gene expression with anti-miRs enables regulation of many genes along defined tissue-specific signaling pathways to enhance angiogenesis. Since it is also unknown how delivery timing of these anti-miR combinations may impact efficacy, we will leverage controlled-release LbL bandages to investigate this. Through this research, I will advance the delivery of nucleic acids with biomaterial systems and the targeting of aberrantly expressed coding and non-coding RNAs to promote healing of diabetic wounds. This work will lay the groundwork for expansion of this platform approach to other diseases of impaired tissue regeneration where timing the delivery to the healing process is critical, such as venous ulcers, mesenteric ischemia, and myocardial infarction.

项目摘要 非愈合溃疡是糖尿病的常见并发症，导致生活质量降低，速度升高 截肢，死亡风险增加以及高昂的医疗费用。不幸的是，当前的治疗仍然存在 过时和不足。在糖尿病中，真皮组织的神经病和微血管变化导致 分子提示失调，导致慢性炎症和血管生成减少，以防止伤口 康复。鉴于脉管系统在供应氧气中的重要性，较差的血管生成特别重要， 营养和全身信号分子。血管生成的损害部分由异常表达驱动 在各个时间尺度上编码的Messenger RNA（mRNA）和非编码microRNA（miRNA）。因此，一个 改变糖尿病性溃疡过程的有前途的方法是直接靶向上调的RNA 在非治疗状态下，使用核酸RNA靶向疗法；但是，交付挑战呈现核 酸治疗在临床上不可行。为了应对这些交付挑战，Hammond Lab已开发并 通过一层（LBL）技术显示了核酸对核酸的自组装静电沉积， 利用了交替电荷的聚电解质的迭代吸附，以在 可调释放动力学的伤口绷带。我建议开发和调查受时间控制的 释放局部提供促进RNA靶向疗法的策略，以促进血管生成和治愈 糖尿病性溃疡。在AIM 1中，我将制定分期释放RNA靶向绷带以促进伤口愈合 由于针对多个目标的上演治疗释放将使绷带可以解决伤口的不同阶段 康复。概念证明的绷带将开发用于洗脱靶向RNA的疗法以刺激血管生成 在炎症和增生性伤口愈合阶段，它将在体外和在 体内糖尿病性溃疡模型的鼠。在AIM 2中，我将确定促血管生成抗MIR的潜在协同作用 （miRNA抑制剂），因为用抗MIRS抑制基因表达可以调节许多基因 定义的组织特异性信号通路以增强血管生成。由于也未知交付时间 这些抗MIR组合可能会影响疗效，我们将利用受控释放的LBL绷带 调查这个。通过这项研究，我将通过生物材料系统和 异常表达的编码和非编码RNA的靶向促进糖尿病伤口的愈合。这 工作将为扩展这种平台方法扩展到其他受损组织的疾病奠定基础 在恢复过程中交付时的再生至关重要，例如静脉溃疡，肠系膜 缺血和心肌梗塞。

项目成果

pH-Responsive, Charge-Reversing Layer-by-Layer Nanoparticle Surfaces Enhance Biofilm Penetration and Eradication.

• DOI: 10.1021/acsbiomaterials.3c00481
• 发表时间: 2023-06
• 期刊: ACS biomaterials science & engineering
• 影响因子: 5.8
• 作者: Elad Deiss‐Yehiely;Gerardo Cárcamo-Oyarce;Adam G. Berger;K. Ribbeck;P. Hammond