Tuned stem cell extracellular vesicles are a novel chronic wound therapeutic

调谐干细胞胞外囊泡是一种新型慢性伤口治疗剂

• 批准号: 10022443
• 负责人: YOLANDA Renee LEA-CURRIE
• 金额: $ 118.32万
• 依托单位: ZEN-BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022443
• 关键词: Abnormal Cell; Address; Affinity; Age; Aging; Allogenic; Animal Model; Atrophic; Biological; Bioreactors; Blood Chemical Analysis; Blood flow; Cell Count; Cell Therapy; Cells; Characteristics; Chronic; Clinical; Complex; Defect; Dermal; Development; Diabetes Mellitus; Dose; Effectiveness; Elderly; Endotoxins; Environment; Failure; Freezing; Future; Genotype; Goals; Growth Factor; Healthcare; Healthcare Systems; Heat-Shock Response; Hematology; Histopathology; Human; Immune response; Immunocompetent; Impaired wound healing; In Vitro; Inflammation; Injections; Intuition; Leg Ulcer; Life; Lipids; Longevity; Measures; Methods; Mixed Lymphocyte Culture Test; Modality; Monitor; Mus; Nucleic Acids; Obesity; Organ; Particle Size; Patients; Phase; Phenotype; Population; Prevalence; Process; Production; Property; Proteins; RNA; Recurrence; Regenerative Medicine; Renal function; Research; Route; Site; Skin wound healing; Sterility; Stress; System; Therapeutic; Time; Tissues; Topical application; Toxic effect; Varicose Ulcer; Venous; Vesicle; Wound models; adult stem cell; age related; aged; aging population; base; cell type; chronic wound; comorbidity; cost; db/db mouse; decubitus ulcer; design; diabetic ulcer; drug discovery; exosome; extracellular vesicles; healing; improved; in vivo; in vivo evaluation; mouse model; non-healing wounds; novel; paracrine; platelet-derived growth factor BB; programs; regenerative therapy; repaired; response; soft tissue; stem cell biology; stem cell therapy; stem cells; tissue regeneration; tissue repair; wound bed; wound closure; wound healing; wound treatment

Project Summary The elderly population is rapidly increasing worldwide and those over 60 years old are expected to comprise 20% of the total population by 2050. These demographic changes will focus healthcare needs on those conditions more prevalent in the elderly. Chronic wounds, such as venous leg ulcers, pressure ulcers and diabetic ulcers are over-represented in the elderly population and even now present a significant healthcare burden. These conditions impact approximately 6.5 million patients annually with a cost to the health care system of over $25B. Rarely occurring in the young, the healing of these chronic wounds is confounded by age-related factors such as reduced blood flow, dermal atrophy, increased inflammation and reduced growth factor responses. The high recurrence rate and failure to respond to current therapies indicates the need for improved regenerative therapeutics that can overcome many of the age-associated defects in the wound healing process. Stem cell therapies represent a compelling means of tissue repair and have demonstrated wound healing and soft tissue regeneration in animal models. However, the intuitive concept that therapeutic stem cells engraft and differentiate at sites of tissue damage is not well supported given the low numbers of cells retained over time at application sites in vivo. This suggests that their mechanisms of action occur through paracrine modalities such as secretion of bioactive vesicles, including exosomes. Hence, exploiting stem cell-derived exosomes as a biologic-derived therapy, rather than delivering transient stem cells to treat chronic wounds, is an enticing approach. Secreted extracellular vesicles (EVs), such as exosomes, are packed with potent pro-repair proteins and RNA cargos that are both cell type- specific, as well as, differentially produced and secreted according to the cellular environment. Based on our successful Phase I project, this Phase II program will continue the development and manufacturing of stem cell-derived EVs specifically produced as a chronic wound therapeutic. We will achieve this goal by the following Aims: 1) Optimize the production of selectively-modified hASC EVs for chronic wound healing, 2) In vivo testing of EVs in chronic wound models to establish optimal dosing and route of administration, and 3) Initiate IND enabling studies. This Phase II research program is designed to identify an optimal manufacturing method of bioactive EVs with in vitro and in vivo efficacy and potency, minimal toxicity and strong clinical and translational potential for the treatment of age-related chronic wounds towards a future IND submission. This potential therapeutic has the unique advantage of harnessing the power of stem cells without the need for utilizing complex cell therapies.

项目概要 全球老年人口迅速增加，60岁以上老年人口预计将占总人口的20% 到 2050 年，总人口将增加。这些人口变化将使医疗保健需求集中在那些在 老年人。慢性伤口，如腿部静脉性溃疡、压力性溃疡和糖尿病性溃疡，在慢性伤口中所占比例过高。 老年人口甚至现在都构成了巨大的医疗负担。这些条件影响大约 6.5 每年 10 万名患者，医疗保健系统的费用超过 25B 美元。年轻人中很少发生，治愈 这些慢性伤口受到与年龄相关的因素的影响，例如血流量减少、真皮萎缩、皮肤老化等。 炎症和生长因子反应减少。复发率高且对当前治疗无效 表明需要改进的再生疗法来克服许多与年龄相关的缺陷 伤口愈合过程。干细胞疗法代表了一种令人信服的组织修复方法，并已证明伤口 动物模型中的愈合和软组织再生。然而，治疗性干细胞移植的直观概念 由于随着时间的推移保留的细胞数量较少，因此在组织损伤部位的分化并没有得到很好的支持。 体内应用部位。这表明它们的作用机制是通过旁分泌方式发生的，例如 分泌生物活性囊泡，包括外泌体。因此，利用干细胞衍生的外泌体作为生物衍生的外泌体 治疗，而不是提供暂时的干细胞来治疗慢性伤口，是一种诱人的方法。分泌细胞外 囊泡 (EV)，例如外泌体，充满了有效的促修复蛋白和 RNA 货物，它们都是细胞类型 特定的，以及根据细胞环境差异产生和分泌的。基于我们的成功 一期项目，二期项目将继续开发和制造干细胞电动汽车 专门生产作为慢性伤口治疗剂。我们将通过以下目标来实现这一目标： 1）优化 生产用于慢性伤口愈合的选择性修饰的 hASC EV，2) 慢性伤口中 EV 的体内测试 建立最佳剂量和给药途径的模型，以及 3) 启动 IND 支持研究。本期二期 研究计划旨在确定体外和体内生物活性电动汽车的最佳制造方法 功效和效力、最小毒性以及治疗与年龄相关的疾病的强大临床和转化潜力 慢性伤口，以利于未来的 IND 提交。这种潜在的治疗方法具有利用 干细胞的力量，无需利用复杂的细胞疗法。