Novel Therapy for Chronic Non-healing Wounds

慢性不愈合伤口的新疗法

• 批准号: 7539221
• 负责人: JAMES W LARRICK
• 金额: $ 14.31万
• 依托单位: PANORAMA RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7539221
• 关键词: Address; Affect; Amino Acids; Beds; Binding; Burn injury; C-terminal; Chronic; Closure; Complication; Diabetes Mellitus; Diabetic Foot; Diabetic mouse; Endopeptidases; Epithelium; Failure; Goals; Healed; Human; Immune system; Infection; Inflammation; Inflammatory Infiltrate; Injury; Laboratories; Leukocytes; Lung; Metabolic syndrome; Modeling; Organ; Organ Culture Techniques; Oryctolagus cuniculus; Patients; Peptide Hydrolases; Phase; Play; Population; Proteins; Resistance; Role; Skin; Stasis Ulcer; Ulcer; United States; Vascularization; Venous; Work; Wound Healing; abstracting; antimicrobial; base; cost; glycemic control; healing; immunoreactivity; in vivo; inhibiting antibody; novel; pandemic disease; preclinical study; wound

DESCRIPTION (provided by applicant): ABSTRACT: A significant need exists to address complications associated with the growing pandemic of diabetes mellitus and metabolic syndrome now estimated to affect >20 million people in the United States (~7% of the population!). Impaired wound repair, a major complication of poor glycemic control, costs >$10 billion annually. Our laboratory first identified and cloned rabbit (Larrick et al., 1991) and then human Cationic Anti- microbial Protein (hCAP18) based on its LPS binding and anti-microbial activities. Over the past 10 years hCAP18 has been shown to be an important component of the innate immune system with broad anti-microbial activity conferred by its C-terminal fragment LL-37. hCAP18 is constitutively produced in leukocytes and is induced in barrier organs (e.g. lung, GI, skin) upon inflammation and infection. Recent work demonstrated a key role of hCAP18 in vascularization and re-epithelialization of skin wounds. High levels of hCAP18 are produced in skin in vivo upon wounding with a peak at 48 h post-injury, declining to pre-injury levels upon wound closure. hCAP18 is detected in the inflammatory infiltrate and in the epithelium migrating over the wound bed. For example, using a noninflammatory ex vivo wound healing model, composed of organ-cultured human skin, Heilbron et al. (2003) showed that treatment with anti-LL-37 antibodies inhibits re-epithelialization. In chronic non-healing wounds, hCAP18 levels are low and immunoreactivity for hCAP18/LL-37 is absent in ulcer edge epithelium. We hypothesize that LL-37 plays a critical role in wound closure and that its absence in chronic wounds impairs re-epithelialization, promotes bacterial colonization and contributes to failure of the wounds to heal. Hence, the overall goal of this proposal is to develop a protease resistance form of LL-37 as a novel therapy for chronic, non-healing wounds. To this end in phase I we will prepare prLL-37, a protease resistant form comprised of D-amino acids, demonstrate resistance to degradation by proteases, and evaluate activity of prLL-37 in a wound healing model using diabetic mice. In phase II we will carry out preclinical studies to support submission of an IND. This therapy will address a major unmet need among patients suffering from burn injuries and chronic non-healing, diabetic foot, decubitus and venous stasis ulcers. ABSTRACT: A significant need exists to address complications associated with the growing pandemic of diabetes mellitus and metabolic syndrome now estimated to affect >20 million people in the United States (~7% of the population!). Impaired wound repair, a major complication of poor glycemic control, costs >$10 billion annually. Our laboratory first identified and cloned rabbit (Larrick et al., 1991) and then human Cationic Anti- microbial Protein (hCAP18) based on its LPS binding and anti-microbial activities. Over the past 10 years hCAP18 has been shown to be an important component of the innate immune system with broad anti-microbial activity conferred by its C-terminal fragment LL-37. hCAP18 is constitutively produced in leukocytes and is induced in barrier organs (e.g. lung, GI, skin) upon inflammation and infection. Recent work demonstrated a key role of hCAP18 in vascularization and re-epithelialization of skin wounds. High levels of hCAP18 are produced in skin in vivo upon wounding with a peak at 48 h post-injury, declining to pre-injury levels upon wound closure. hCAP18 is detected in the inflammatory infiltrate and in the epithelium migrating over the wound bed. For example, using a noninflammatory ex vivo wound healing model, composed of organ-cultured human skin, Heilbron et al. (2003) showed that treatment with anti-LL-37 antibodies inhibits re-epithelialization. In chronic non-healing wounds, hCAP18 levels are low and immunoreactivity for hCAP18/LL-37 is absent in ulcer edge epithelium. We hypothesize that LL-37 plays a critical role in wound closure and that its absence in chronic wounds impairs re-epithelialization, promotes bacterial colonization and contributes to failure of the wounds to heal. Hence, the overall goal of this proposal is to develop a protease resistance form of LL-37 as a novel therapy for chronic, non-healing wounds. To this end in phase I we will prepare prLL-37, a protease resistant form comprised of D-amino acids, demonstrate resistance to degradation by proteases, and evaluate activity of prLL-37 in a wound healing model using diabetic mice. In phase II we will carry out preclinical studies to support submission of an IND. This therapy will address a major unmet need among patients suffering from burn injuries and chronic non-healing, diabetic foot, decubitus and venous stasis ulcers.

描述（由申请人提供）：摘要：存在解决与糖尿病和代谢综合征日益流行相关的并发症的显著需求，目前估计在美国影响> 2000万人（约占人口的7%!）。伤口修复受损是血糖控制不良的主要并发症，每年花费超过100亿美元。我们的实验室首先鉴定并克隆了兔子（Larrick等人，1991），然后是人阳离子抗微生物蛋白（hCAP 18），基于其LPS结合和抗微生物活性。在过去的10年中，hCAP 18已被证明是先天免疫系统的重要组分，其C-末端片段LL-37赋予广泛的抗微生物活性。hCAP 18在白细胞中组成性产生，并且在炎症和感染时在屏障器官（例如肺、GI、皮肤）中被诱导。最近的工作证明了hCAP 18在皮肤伤口的血管化和再上皮化中的关键作用。受伤后，体内皮肤中产生高水平的hCAP 18，在损伤后48小时达到峰值，在伤口闭合后下降至损伤前水平。hCAP 18在炎性浸润物和在伤口床上迁移的上皮中检测到。例如，使用由器官培养的人皮肤组成的非炎性离体伤口愈合模型，Heilbron等人（2003）显示用抗LL-37抗体治疗抑制上皮再形成。在慢性不愈合伤口中，hCAP 18水平较低，溃疡边缘上皮中不存在hCAP 18/LL-37的免疫反应性。我们假设LL-37在伤口闭合中起关键作用，并且其在慢性伤口中的缺失损害再上皮化，促进细菌定植并导致伤口愈合失败。因此，该提案的总体目标是开发LL-37的蛋白酶抗性形式作为慢性不愈合伤口的新疗法。为此，在阶段I中，我们将制备prLL-37，一种由D-氨基酸组成的蛋白酶抗性形式，证明对蛋白酶降解的抗性，并使用糖尿病小鼠在伤口愈合模型中评价prLL-37的活性。在第二阶段，我们将开展临床前研究，以支持提交IND。这种疗法将解决烧伤和慢性不愈合、糖尿病足、褥疮和静脉淤滞性溃疡患者的主要未满足需求。摘要：存在解决与糖尿病和代谢综合征的日益增长的流行病相关的并发症的显著需求，目前估计在美国影响> 2000万人（约7%的人口!）。伤口修复受损是血糖控制不良的主要并发症，每年花费超过100亿美元。我们的实验室首先鉴定并克隆了兔子（Larrick等人，1991），然后是人阳离子抗微生物蛋白（hCAP 18），基于其LPS结合和抗微生物活性。在过去的10年中，hCAP 18已被证明是先天免疫系统的重要组分，其C-末端片段LL-37赋予广泛的抗微生物活性。hCAP 18在白细胞中组成性产生，并且在炎症和感染时在屏障器官（例如肺、GI、皮肤）中被诱导。最近的工作证明了hCAP 18在皮肤伤口的血管化和再上皮化中的关键作用。受伤后，体内皮肤中产生高水平的hCAP 18，在损伤后48小时达到峰值，在伤口闭合后下降至损伤前水平。hCAP 18在炎性浸润物和在伤口床上迁移的上皮中检测到。例如，使用由器官培养的人皮肤组成的非炎性离体伤口愈合模型，Heilbron等人（2003）显示用抗LL-37抗体治疗抑制上皮再形成。在慢性不愈合伤口中，hCAP 18水平较低，溃疡边缘上皮中不存在hCAP 18/LL-37的免疫反应性。我们假设LL-37在伤口闭合中起关键作用，并且其在慢性伤口中的缺失损害再上皮化，促进细菌定植并导致伤口愈合失败。因此，该提案的总体目标是开发LL-37的蛋白酶抗性形式作为慢性不愈合伤口的新疗法。为此，在阶段I中，我们将制备prLL-37，一种由D-氨基酸组成的蛋白酶抗性形式，证明对蛋白酶降解的抗性，并使用糖尿病小鼠在伤口愈合模型中评价prLL-37的活性。在第二阶段，我们将开展临床前研究，以支持提交IND。这种疗法将解决烧伤和慢性不愈合、糖尿病足、褥疮和静脉淤滞性溃疡患者的主要未满足需求。